[0001] The disclosure relates generally to biology and medicine, and more particularly it relates to Peptide Tyrosine-Tyrosine (PYY) analogs that can bind a neuropeptide Y (NPY) receptor such as the NPY2 receptor, as well as compositions including the same and their therapeutic use in treating obesity and obesity-related diseases and disorders such as type II diabetes (T2DM).

[0002] PYY is a member of the pancreatic polypeptide (PP) family and is involved in modulating food intake and energy expenditure following a meal (see, Tatemoto (1982) Proc. Natl. Acad. Sci. 79:2514-2518). PYY is secreted by L cells of the gastrointestinal track and has two main endogenous forms - PYYi-36 (SEQ ID NO: l) and PYY3-36 (SEQ ID NO:2). PYYi -36 predominates over PYY3-36 during fasting, whereas PYY3-36 predominates over PYYi-36 following feeding. Dipeptidyl peptidase-IV (DPP-IV) hydrolyzes PYYi-36 at a Pro2-Ile3 bond to produce PYY3-36, which is more selective for the NPY2 receptor than PYYi-36.

[0003] Plasma PYY3 -36 concentration typically increases within 15 minutes of food intake, peaks within 60-90 minutes, and remains elevated for up to 6 hours before returning to baseline (see, Adrian et al. (1985) Gastroenterology 89: 1070-1077; and De Silva & Bloom (2012) Gut Liver 6: 10-20). In this manner, PYY3-36 is believed to impact appetite via its direct central effect and also via its effect on gut motility (i.e., its anorectic effect). Additionally, PYY3-36 is believed to mediate insulin sensitivity to thereby help lower blood glucose (i.e., its sensitization effect).

[0004] PYY3 -36 has been investigated as a potential therapeutic agent for body-weight regulation in view of its anorectic effects, especially for treating obesity and its associated diseases and disorders, including T2DM and cardiovascular diseases (see, e.g. , Intl. Patent Application Publication No. 2002/47712; and Schwartz & Morton (2002) Nature 418:595-597).

[0005] Unfortunately, exogenously administered PYY3-36 has a short half-life (e.g, about 10-15 minutes) due to proteases and other clearance mechanisms (see, Lluis et al. (1989) Rev. Esp. Fisiol. 45:377-384; and Torang etal. (2016 )Am. J. Physiol. Regul. Integr. Comp. Physiol. 3 l0:R866-R874), which presents challenges when using it as a therapeutic agent.

With such a short half-life, PYY3 -36 should be administered at least once-daily to exert a therapeutic effect, which is inconvenient for an individual in need thereof. Efforts therefore have been made to increase PYY3-36’s half-life and/or to increase its NPY2 receptor selectivity. For example, Rubinstein et al. describe PYY analogs having a 9-fluorenylmethoxy-carbonyl (Fmoc) or a 2-sulfo-9-fluorenyl-methoxycarbonyl (FMS) radical to increase half-life (see, Inti. Patent Application Publication No. WO 2004/089279). Moreover, DeCarr et al. describe PYY analogs having amino-terminally linked PEG moieties to increase half-life (see, DeCarr et al. (2007) Bioorg. Med. Chem. Lett. 17: 1916-1919; see also, Ortiz et al. (2007) J. Pharmacol. Exp. Ther. 323 :692-700). Furthermore, Kofoed et al. describe PYY analogs having albumin-binding side chains, at least one modified residue close to PYY’s cleavage site (e.g. an N-m ethyl amino acid analog of an amino acid residue of interest), a N-glycine, and/or an arginine mimetic to increase half-life (see, Inti. Patent Application Publication No. WO 2011/033068).

[0006] Despite significant increases in understanding PYY3-36’ s role in metabolism, there remains a need for additional PYY analogs, especially PYY analogs having improved potency and selectivity at the NPY2 receptor.

[0007] As noted above, additional PYY analogs for therapeutic uses are needed. To address this need, the disclosure first describes PYY analogs that include a base amino acid sequence of (with respect to the numbering of native, human PYYi-36 (SEQ ID NO: 1)): 3PKPEX7PX9XioDASPEEXi7Xi8RYYX22X23LRHYLNX3oLTRQRY36 (Formula I), where X7 is any amino acid with a functional group available for conjugation and the functional group is conjugated to a C16-C22 fatty acid, X9 is E or G, X10 is E or K, Xl7 is L or W, Xi8 is N or Q, X22 is A or I, X23 is E, D or S, and X30 is E or W (SEQ ID NO:3), and where a carboxy-terminal (C-terminal) amino acid optionally is amidated.

[0008] In certain instances, the amino acid with the functional group available for conjugation at position X7 can be C, D, E, K or Q. In particular instances, the amino acid with the functional group available for conjugation at position X7 is K, and the amino acid sequence can be one of the following:

3PKPEKPGEDASPEEWQRYYAELRHYLNWLTRQRY36 (SEQ ID NO:4),

3PKPEKPGEDASPEEWQRYYAELRHYLNELTRQRY36 (SEQ ID NO: 5),

3PKPEKPEEDASPEEWQRYYIELRHYLNWLTRQRY36 (SEQ ID NO: 6),

3PKPEKPGKDASPEEWNRYYADLRHYLNWLTRQRY36 (SEQ ID NO: 7), or

3PKPEKPGEDASPEELQRYYASLRHYLNWLTRQRY36 (SEQ ID NO: 8).

[0009] In some instances, the C16-C22 fatty acid is conjugated to the amino acid with the functional group available for conjugation via a linker. In certain instances, the C16-C22 fatty acid has a structure of -C0-(CH2)a-C02H, where a is an integer between 16 to 22. In particular instances, the fatty acid is a Ci8 diacid or a C20 diacid such as palmitic acid, stearic acid, arachidic acid or eicosanoic acid, especially a saturated Ci8 diacid or C20 diacid. Likewise, and in some instances, the linker can be one or more units of [2-(2-amino-ethoxy)-ethoxy)]-acetic acid (AEEA), aminohexanoic acid (Ahx), glutamic acid (E), g-glutamic acid (gE) or combinations thereof.

[0010] In particular instances, the PYY analog can be one of the following:

O

2
(SEQ ID NO: 12), or

P K P E

(SEQ ID NO: 13).

[0011] In some instances, the base structure of the PYY analogs herein further can include the two amino-terminal (N-terminal) amino acids of native, human PYYi-% (SEQ ID NO: l), which subsequently can be processed in vivo to a PYY3-36 analog (i.e., the N-terminal“YP” residues of SEQ ID NO: l can be cleaved in vivo from any one of the PYY analogs).

[0012] In some instances, the PYY analogs have a charge of greater than -2, especially -3 or -4.

[0013] In some instances, the PYY analogs have a binding affinity at the human NPY2 receptor that is greater than that of human PYY3-36 (SEQ ID NO:2), such as from about 2-fold greater to about lO-fold greater, especially about 2-fold greater to about 3-fold greater.

[0014] In some instances, the PYY analogs have a half-life that is longer than that of human PYY3-36 (SEQ ID NO:2), such as from about 5 hours to about 24 hours longer, especially about 12 hours.

[0015] Second, pharmaceutical compositions are described that include at least one PYY analog herein or a pharmaceutically acceptable salt thereof ( e.g ., trifluroacetate salts, acetate salts or hydrochloride salts) and a pharmaceutically acceptable carrier. In some instances, the pharmaceutical compositions further can include carriers, diluents and/or excipients.

[0016] Moreover, the pharmaceutical compositions can include an additional therapeutic agent such as, for example, other antidiabetic or weight loss agents, especially an incretin. In some instances, the incretin can be glucagon (GCG) or a GCG analog. In other instances, the incretin can be glucagon-like peptide-l (GLP-l), GLP-l (7-36)amide or a GLP-l analog. In other instances, the incretin can be gastric inhibitory peptide (GIP) or a GIP analog. In other instances, the incretin can be a dual receptor agonist such as oxyntomodulin (OXM) or an OXM analog, GLP-l/GCG or GIP/GLP-l . In other instances, the incretin can be an incretin analog having triple receptor activity (i.e., incretin analogs with activity at each of the GIP, GLP-l and GCG receptors). In other instances, the additional therapeutic agent can be a DPP-IV inhibitor.

[0017] Third, methods are described for using the PYY analogs herein, especially for using the PYY analogs to treat obesity and obesity-related diseases and disorders such as T2DM. The methods include at least a step of administering to an individual in need thereof an effective amount of a PYY analog as described herein or a pharmaceutically acceptable salt thereof.

[0018] In some instances, the PYY analog can be subcutaneously (SQ) administered to the individual. Likewise, and in some instances, the PYY analog can be administered daily, every other day, three times a week, two times a week, one time a week (i.e., weekly), biweekly (i.e., every other week), or monthly. In certain instances, the PYY analog can be administered SQ every other day, SQ three times a week, SQ two times a week, SQ one time a week, SQ every other week, or SQ once a month. In particular instances, the PYY analog is administered SQ one time a week (QW).

[0019] Alternatively, the PYY analog can be orally administered to the individual. As above, the PYY analog can be administered daily, every other day, three times a week, two times a week, one time a week (i.e., weekly), biweekly (i.e., every other week), or monthly. In certain instances, the PYY analog can be administered orally every other day, orally three times a week, orally two times a week, orally one time a week, orally every other

week, or orally once a month. In particular instances, the PYY analog is administered orally one time a week.

[0020] The methods also can include administering the at least one PYY analog in combination with an effective amount of an additional therapeutic agent such as a DPP-IV inhibitor or an incretin ( e.g ., GCG or a GCG analog, GLP-l, GLP-l (7-36)amide or a GLP-1 analog, GIP or a GIP analog, OXM or an OXM analog, GIP/GLP-l, GLP-l/GCG, or an incretin having triple receptor activity). The DPP-IV inhibitor or incretin can be administered simultaneously, separately or sequentially with the PYY analog.

[0021] In some instances, the DPP-IV inhibitor or incretin can be administered with a frequency same as the PYY analog (i.e., every other day, twice a week, or even weekly). In other instances, the DPP-IV inhibitor or incretin is administered with a frequency distinct from the PYY analog. In other instances, the DPP-IV inhibitor or incretin is administered QW. In still other instances, the PYY analog is administered SQ, and the DPP-IV inhibitor or the incretin can be administered orally.

[0022] In some instances, the individual is obese or overweight. In other instances, the individual is a person with diabetes (PwD), especially T2DM. In certain instances, the individual is obese with T2DM or overweight with T2DM.

[0023] The methods also may include steps such as measuring or obtaining the individual’s weight and/or blood glucose and/or hemoglobin Ale (HbAlc) and comparing such obtained values to one or more baseline values or previously obtained values to assess the effectiveness of treatment.

[0024] The methods also may be combined with diet and exercise and/or may be combined with additional therapeutic agents other than those discussed above.

[0025] Fourth, uses are described for the PYY analogs herein in treating obesity and obesity-related diseases and disorders such as T2DM, which optionally can be administered simultaneously, separately or sequentially (i.e., in combination) with a DPP-IV inhibitor and/or an incretin such as GCG or a GCG analog, GLP-l, GLP-l (7-36)amide or a GLP-l analog, GIP or a GIP analog, OXM or an OXM analog, GIP/GLP-l, GLP-l/GCG, or even an incretin having triple receptor activity.

[0026] Fifth, uses are described for the PYY analogs herein in manufacturing a medicament for treating obesity and obesity-related diseases and disorders such as T2DM, where the medicament optionally may further include a DPP-IV inhibitor and/or an incretin such as GCG or a GCG analog, GLP-l, GLP-l (7-36)amide or a GLP-l analog, GIP or a GIP analog, OXM or an OXM analog, GIP/GLP-l, GLP-l/GCG, or even an incretin having triple receptor activity.

[0027] One advantage of the PYY analogs herein is that they not only can facilitate weight loss but also can lower glucose. In this manner, individuals, especially those susceptible to or having T2DM, can delay progressing to exogenous insulin and can maintain target HbAlc goals. Moreover, the PYY analogs herein can enhance glycemic control by improving insulin sensitization. Combined, GIP/GLP-l and PYY analog can be used for both glucose control (incretin + potential insulin sensitizer) and weight loss (synergistic). In particular, the PYY analogs herein can cause an up to about 12% weight loss alone when administered to an individual in need thereof and can cause an up to about 25% weight loss in connection with an additional therapeutic agent such as an incretin when administered to an individual in need thereof.

[0028] Another advantage of the PYY analogs herein is that they can have a half-life of up to about 24 hours, thereby allowing for once weekly administration.

[0029] Another advantage of the PYY analogs herein is that they have increased physico-chemical stability and compatibility when compared to native, human PYY3-36 (SEQ ID NO:2) and increased compatibility in a formulation with incretins when compared to native, human PYY3-36 (SEQ ID NO:2).

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art to which the disclosure pertains. Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the PYY analogs, pharmaceutical compositions and methods, the preferred methods and materials are described herein.

[0031] Moreover, reference to an element by the indefinite article“a” or“an” does not exclude the possibility that more than one element is present, unless the context clearly requires that there be one and only one element. The indefinite article“a” or“an” thus usually means“at least one.”

[0032] Definitions

[0033] As used herein,“about” means within a statistically meaningful range of a value or values such as, for example, a stated concentration, length, molecular weight, pH, sequence identity, time frame, temperature, volume, etc. Such a value or range can be within an order of magnitude typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The allowable variation encompassed by“about” will depend upon the particular system under study, and can be readily appreciated by one of skill in the art.

[0034] As used herein,“amino acid” means a molecule that, from a chemical standpoint, is characterized by the presence of one or more amine groups and one or more carboxylic acid groups and may contain other functional groups. As is known in the art, there is a set of twenty amino acids that are designated as standard amino acids and that are used as building blocks for most of the peptides/proteins produced by any living being.

[0035] As used herein,“amino acid with a functional group available for conjugation” means any natural or unnatural amino acid with a functional group that may be conjugated to a fatty acid by way of, for example, a linker. Examples of such functional groups include, but are not limited to, alkynyl, alkenyl, amino, azido, bromo, carboxyl, chloro, iodo and thiol groups. Additionally, examples of natural amino acids including such functional groups include C (thiol), D (carboxyl), E (carboxyl), K (amino) and Q (amide).

[0036] As used herein,“analog” means a compound, such as a synthetic peptide or polypeptide, that activates a target receptor and that elicits at least one in vivo or in vitro effect elicited by a native agonist for that receptor.

[0037] As used herein,“anorectic effect” means an ability of the PYY analogs herein to reduce appetite, resulting in lower food consumption and ultimately leading to weight loss. Anorectic effect also may refer to an ability of the PYY analogs herein to increase gut motility.

[0038] As used herein,“C16-C22 fatty acid” means a carboxylic acid having between 16 and 22 carbon atoms. The C16-C22 fatty acid suitable for use herein can be a saturated monoacid or a saturated diacid (“diacids” have a carboxyl group on each end).

[0039] As used herein,“AETC” means area under the curve.

[0040] As used herein,“effective amount” means an amount, concentration or dose of one or more PYY analogs herein, or a pharmaceutically acceptable salt thereof which, upon single or multiple dose administration to an individual in need thereof, provides a desired effect in such an individual under diagnosis or treatment (z.e., may produce a clinically measurable difference in a condition of the individual such as, for example, a reduction in blood glucose, a reduction in HbAlc, and/or a reduction in weight or body fat). An effective amount can be readily determined by one of skill in the art by using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered, including, but not limited to, the species of mammal, its size, age and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual, the particular PYY analog administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.

[0041] As used herein, “half-maximal effective concentration” or“ECso” means a concentration of compound that results in 50% activation/stimulation of an assay endpoint, such as a dose-response curve ( e.g ., cAMP).

[0042] As used herein,“in combination with” means administering at least one of the PYY analogs herein either simultaneously, sequentially or in a single combined formulation with one or more additional therapeutic agents.

[0043] As used herein,“incretin analog” means a peptide or polypeptide having structural similarities with, but multiple differences from, each of GIP, GLP-l, GCG and OXM, especially native, human GIP, GLP-l, GCG and OXM. Some incretin analogs also have affinity for and activity at two or even each of the GIP, GLP-l and GCG receptors (i.e., agonist activity at two receptors such as in OXM, GIP/GLP-l or GLP-l/GCG, or even agonist activity at all three receptors).

[0044] As used herein,“individual in need thereof’ means a mammal, such as a human, with a condition, disease, disorder or symptom requiring treatment or therapy, including for example, those listed herein. In particular, the preferred individual to be treated is a human.

[0045] As used herein,“long-acting” means that binding affinity and activity of a PYY analog herein continues for a period of time greater than native, human PYYl-36 (SEQ ID NO: l) and/or native, human PYY3-36 (SEQ ID NO:2), allowing for dosing at least as infrequently as once daily or even thrice-weekly, twice-weekly, once-weekly, or monthly. The time action profile of the PYY analogs herein may be measured using known pharmacokinetic test methods such as those described in the Examples below.

[0046] As used herein,“non-standard amino acid” means an amino acid that may occur naturally in cells but does not participate in peptide synthesis. Non-standard amino acids can be constituents of a peptide and often times are generated by modification of standard amino acids in the peptide {i.e., via post-translational modification). Non-standard amino acids can include D-amino acids, which have an opposite absolute chirality of the standard amino acids above.

[0047] As used herein,“obese” or“obesity” means a condition in which an individual has a body mass index (BMI) that is >30.0 kg/m2. See generally ,“Overweight & Obesity” by the Center for Disease Control and Prevention available at cdc.gov/obesity/adult/defming.html; and“Definitions & Facts for Adult Overweight & Obesity” by the National Institutes of Health at iddk.nih.gov/health-information/weight-management/adult-overweight-obesity/defmition-facts.

[0048] As used herein,“obesity-related disease or disorder” means any diseases or disorders that are induced/exacerbated by obesity including, but not limited to, angina pectoris, cardiovascular disease, cholecystitis, cholelithiasis, congestive heart failure, dyslipidemia, fatty liver disease, fertility complications, glucose intolerance, gout, hypertension, hypothyroidism, hyperinsulinemia, insulin resistance, osteoarthritis, polycystic ovary syndrome (PCOS), pregnancy complications, psychological disorders, sleep apnea and other respiratory problems, stress urinary incontinence stroke, T2DM, uric acid nephrolithiasis (kidney stones), and cancer of the breast, colon, endometrium, esophagus, gall bladder, kidney, prostate and rectum.

[0049] As used herein,“overweight” means a condition in which an individual has a BMI that is about 25.0 kg/m2 to <30 kg/m2. See , id.

[0050] As used herein,“PYY” means Peptide YY obtained or derived from any species, such as a mammalian species, especially a human. PYY includes both the native PYY {i.e., full-length) and variations thereof {i.e., additions, deletions and/or substitutions of native PYY). Specific PYYs include, but are not limited to, native, human PYYi-36 (SEQ ID NO: l) and native, human PYY3-36 (SEQ ID NO:2).

[0051] As used herein,“PYY analog” or“PYY analogs” means a PYY-like peptide or polypeptide that elicits one or more effects of native PYY at one or more NPY receptors such as the NPY2 receptor. In some instances, the PYY analogs herein can bind to a NPY receptor, especially the human NPY2 receptor, with higher or lower affinity but

demonstrate a longer half-life in vivo or in vitro when compared to native PYY, especially human PYY such as native, human PYYi-36 (SEQ ID NO: l) and native, human PYY3-36 (SEQ ID NO:2). In this manner, the PYY analogs herein are synthetic compounds that act as NPY2 receptor agonists.

[0052] As used herein,“saturated” means the fatty acid contains no carbon-carbon double or triple bonds.

[0053] As used herein,“sensitizing effect” means an ability of the PYY analogs herein to increase the effect of insulin and thereby help lower blood glucose.

[0054] As used herein,“treating” or“to treat” means attenuating, restraining, reversing, slowing or stopping progression or severity of an existing condition, disease, disorder or symptom.

[0055] Certain abbreviations are defined as follows: “ACR” refers to urine albumin/urine creatinine ratio;“amu” refers to atomic mass unit;“tBoc” refers to tert-butoxycarbonyl;“cAMP” refers to cyclic adenosine monophosphate;“DMF” refers to dimethylformamide;“DMSO” refers to dimethyl sulfoxide;“EIA/RIA” refers to enzyme immunoassay/radioimmunoassay;“hr” refers to hour;“HTRF” refers to homogenous time-resolved fluorescent;“IV” refers to intravenous;“kE)a” refers to kilodaltons;“LC-MS” refers to liquid chromatography-mass spectrometry;“MS” refers to mass spectrometry; “OtBu” refers to O-tert-butyl; “Pbf’ refers to NG-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; “RP-HPLC” refers to reversed-phase high performance liquid chromatography; “SQ” refers to subcutaneous; “SEM” refers to standard error of the mean;“TFA” refers to trifluoroacetic acid; and“Tit” refers to Trityl.

[0056] PYY Analogs

[0057] The PYY analogs herein have structural similarities to, but many structural differences, from native PYY peptides. For example, when compared to native, human P YY i-36 (SEQ ID NO: l) and/or native, human PYY3-36 (SEQ ID NO:2), the PYY analogs described herein include modifications at one or more of positions 3, 7, 9, 10, 17, 18, 22, 23, 30 and 31 with respect to the numbering of native, human PYYi-36 (SEQ ID NO: 1). In certain instances, exemplary amino acid sequences of the PYY analogs herein include (specific changes relative to corresponding residue of native, human PYY (SEQ ID NO: l) are in bold):

3PKPEX7PX9XioDASPEEXi7Xi8RYYX22X23LRHYLNX3oLTRQRY36 (SEQ ID NO:3), 3PKPEKPGEDASPEEWQRYYAELRHYLNWLTRQRY36 (SEQ ID NO:4),

3PKPEKPGEDASPEEWQRYYAELRHYLNELTRQRY36 (SEQ ID NO: 5),

3PKPEKPEEDASPEEWQRYYIELRHYLNWLTRQRY36 (SEQ ID NO: 6),

3PKPEKPGKDASPEEWNRYYADLRHYLNWLTRQRY36 (SEQ ID NO: 7), and

3PKPEKPGEDASPEELQRYYASLRHYLNWLTRQRY36 (SEQ ID NO: 8).

[0058] The PYY analogs herein result in sufficient activity at the human NPY2 receptor but insufficient activity at the NPY1, NPY4 and NPY5 receptors. Likewise, the PYY analogs herein have beneficial attributes relevant to their developability as therapeutic treatments, including improved solubility in aqueous solutions, improved chemical and physical formulation stability, extended pharmacokinetic profile, and minimized potential for immunogenicity.

[0059] In some instances, the PYY analogs herein are amidated at a C-terminal amino acid to affect stability. In addition to the changes described herein, the analogs may include one or more additional amino acid modifications, provided, however, that the analogs remain capable of binding to and activating the human NPY2 receptor.

[0060] The PYY analogs herein further include a fatty acid conjugated, for example, by way of a linker to a natural or unnatural amino acid with a functional group available for conjugation (z.e.,“acylation”). In some instances, the amino acid with a functional group available for conjugation can be C, D, E, K and Q. In particular instances, the amino acid with the functional group available for conjugation is K, where conjugation is to an e-amino group of a K side chain.

[0061] Here, acylation of the PYY analogs is at position 7 when compared to native, human PYY i-36 (SEQ ID NO: 1). In this manner, the fatty acid can act as an albumin binder to provide for longer-acting analogs.

[0062] With respect to the fatty acid, it can be chemically conjugated to the functional group of the amino acid available for conjugation either by a direct bond or by a linker. The length and composition of the fatty acid impacts the half-life of the PYY analogs, the in vivo potency of the PYY analogs, and the solubility and stability of the PYY analogs. Conjugation to a C16-C22 saturated fatty monoacid or diacid thereby results in PYY analogs that exhibit desirable half-life, desirable in vivo potency, and desirable solubility and stability characteristics.

[0063] Exemplary saturated C 16-C22 fatty acids for use herein include, but are not limited to, hexadecanoic acid (i.e., palmitic acid, Ci6 monoacid), hexadecanedioic acid (Ci6 diacid), heptadecanoic acid (i.e., margaric acid, C 17 monoacid), heptadecanedioic acid (C17 diacid), stearic acid (Ci8 monoacid), octadecanedioic acid (C ix diacid), nonadecylic acid (i.e., nonadecanoic acid, C 19 monoacid), nonadecanedioic acid (C19 diacid), eicosanoic acid (i.e., arachadic acid, C20 monoacid), eicosanedioic acid (C20 diacid), heneicosanoic acid (i.e., heneicosylic acid, C21 monoacid), heneicosanedioic acid (C21 diacid), docosanoic acid (i.e., behenic acid, C22 monoacid), docosanedioic acid (C22 diacid), and branched and substituted derivatives thereof. In certain instances, the C 16-C22 fatty acid can be a saturated C ix monoacid, a saturated Ci8 diacid, a saturated C 19 monoacid, a saturated C 19 diacid, a saturated C20 monoacid, a saturated C20 diacid, and branched and substituted derivatives thereof. In particular instances, the C16-C22 fatty acid can be palmitic acid or hexadeconic acid, stearic acid or octadeconic acid, or arachidic acid or eicosanoic acid.

[0064] To assist in conjugating a fatty acid to a natural or unnatural amino acid with the functional group available for conjugation, the PYY analogs herein can include a linker. In some instances, the linker can be at least one of AEEA, Ahx, E or gE, as well as combinations thereof.

[0065] When the linker includes the amino acids, it can have one to four E or gE amino acid residues. In some instances, the linker can include one or two E and/or gE amino acid residues. For example, the linker can include either one or two E and/or gE amino acid residues. In other instances, the linker can include one to four amino acid residues (such as, for example, E or gE amino acids) used in combination with AEEA or Ahx. Specifically, the linker can be combinations of E and gE amino acid residues with AEEA or Ahx. In still other instances, the linker can be combinations of one or two gE amino acid residues and one or two AEEA or Ahx. In particular instances, the linker can be an (AEEA)2·gE moiety, an Ahx*E*yE moiety, or an AEEA·gE moiety.

[0066] Exemplary linker-fatty acid moieties can include (AEEA)2*yE»C2o diacid, Ahx*E*“;/E*C ix diacid, or AEEA*yE*Cix diacid. The structural features of these linker-fatty acid moieties result in analogs having improved half-life when compared to native, human P YY i-36 (SEQ ID NO: 1) or native, human PYY3-36 (SEQ ID NO:2).

[0067] Taken together, exemplary PYY analogs are:

2
(SEQ ID NO: 12), or

[0068] Although the PYY analogs are described as having thirty-four amino acids like that of native, human PYY3-36 (SEQ ID NO:2), it is contemplated that the PYY analogs herein can have an amino acid sequence based upon native, human PYYi-36 (SEQ ID NO: l). That is, the PYY analogs can include the two N-terminal amino acids (i.e., the “YP” residues of positions 1 and 2 of SEQ ID NO: l) of native, human PYYi-36 (SEQ ID NO: l), which subsequently can be cleaved in vivo when administered to an individual as would occur when native, human PYY 1-30 (SEQ ID NO: 1) is endogenously released.

[0069] Half-life of the PYY analogs herein may be measured using techniques known in the art including, for example, those described in the Examples below. Likewise, affinity of the PYY analogs herein for each of the various human NPY receptors (e.g, NPY2R, NPY5R) may be measured using techniques known in the art for measuring receptor binding levels including, for example, those described in the Examples below, and is commonly expressed as an inhibitory constant (Ki) value. Moreover, activity of the PYY analogs herein at each of the receptors also may be measured using techniques known in the art, including, for example, the in vitro activity assays described below, and is commonly expressed as an EC50 value.

[0070] As a result of the modifications described above, the PYY analogs herein have a half-life that is longer than that of native, human PYY3-36 (SEQ ID NO:2). For example, the PYY analogs can have a half-life from about 5 hours to about 24 hours, from about 6 hours to about 23 hours, from about 7 hours to about 22 hours, from about 8 hours to about 21 hours, from about 9 hours to about 20 hours, from about 10 hours to about 19 hours, from about 11 hours to about 18 hours, from about 12 hours to about 17 hours, from about 13 hours to about 16 hours, or even from about 14 hours to about 15 hours. Alternatively, the PPY analogs herein can have a half-life that is about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or even about 24 hours, especially about 12 hours.

[0071] Likewise, the PYY analogs herein have a binding affinity at the NPY2 receptor that is greater than that of native, human PYY3-36 (SEQ ID NO:2), such as from about 2-fold to about lO-fold. Alternatively, the PYY analogs herein can have a binding affinity up to about 2-fold greater, about 3 -fold greater, about 4-fold greater, about 5-fold greater, about 6-fold greater, about 7 fold-greater, about 8-fold greater, about 9-fold greater, or even about lO-fold greater, especially 2-fold greater to 3 -fold greater, than that of native, human PYY3-36 (SEQ ID NO:2).

[0072] Pharmaceutical Compositions

[0073] The PYY analogs herein can be formulated as pharmaceutical compositions, which can be administered by parenteral routes ( e.g ., intravenous, intraperitoneal, intramuscular, subcutaneous or transdermal). Such pharmaceutical compositions and techniques for preparing the same are well known in the art. See , e.g. , Remington,“The Science and Practice of Pharmacy” (D.B. Troy ed., 2lst Edition, Lippincott, Williams & Wilkins, 2006). In particular instances, the PYY analogs are administered SQ. Alternatively, however, the PYY analogs can be formulated in forms for other pharmaceutically acceptable routes such as, for example, tablets or other solids for oral administration; time release capsules; and any other form currently used, including creams, lotions, inhalants and the like.

[0074] To improve their in vivo compatibility and effectiveness, the PYY analogs herein may be reacted with any of a number of inorganic and organic acids/bases to form pharmaceutically acceptable acid/base addition salts. Pharmaceutically acceptable salts and common methodologies for preparing them are well known in the art (see, e.g., Stahl et al,“Handbook of Pharmaceutical Salts: Properties, Selection and Use,” 2nd Revised Edition (Wiley-VCH, 2011)). Pharmaceutically acceptable salts for use herein include sodium, trifluoroacetate, hydrochloride and acetate salts.

[0075] The PYY analogs herein may be administered by a physician or self-administered using an injection. It is understood the gauge size and amount of injection volume can be readily determined by one of skill in the art. However, the amount of injection volume can be < about 2 mL or even < about 1 mL, and the needle gauge can be > about 27 G or even > about 29 G.

[0076] The disclosure also provides and therefore encompasses novel intermediates and methods useful for synthesizing the PYY analogs herein, or a pharmaceutically acceptable salt thereof. The intermediates and PYY analogs herein can be prepared by a variety of methodologies that are well known in the art. For example, a method using chemical synthesis is illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways to prepare the PYY analogs described herein. The reagents and starting materials are readily available to one of skill in the art.

[0077] The PYY analogs herein are generally effective over a wide dosage range. Exemplary doses of the PYY analogs herein or of pharmaceutical compositions including the same can be milligram (mg), microgram (pg), nanogram (ng) or picrogram (pg) amounts per kilogram (kg) of an individual. In this manner, a daily dose can be from about 1 pg to about 100 mg.

[0078] Here, the effective amount of the PYY analog in a pharmaceutical composition can be a dose of about 0.25 mg to about 5.0 mg. One of skill in the art, however, understands that in some instances the effective amount (z.e., dose/dosage) may be below the lower limit of the aforesaid range and be more than adequate, while in other cases the effective amount may be a larger doses and may be employed with acceptable side effects.

[0079] In addition to the PYY analog, the pharmaceutical composition also can include an additional therapeutic agent, especially other antidiabetic or weight loss agents. In some instances, the additional therapeutic agent can be at least one of an incretin or a DPP-IV inhibitor. Exemplary incretins include, but are not limited to, GCG, GLP-l, GLP-l (7-36)amide, GIP, OXM, a GCG analog, a GLP-l analog, a GIP analog, an OXM analog, a GIP/GLP-l, a GLP-l/GCG, or even an incretin analog having triple receptor activity.

[0080] In this manner, the pharmaceutical composition can include an effective amount of a PYY analog of SEQ ID NO: 9 and an incretin or a DPP-IV inhibitor, an effective amount of a PYY analog of SEQ ID NO: 10 and an incretin or a DPP-IV inhibitor, an effective amount of a PYY analog of SEQ ID NO: 11 and an incretin or a DPP-IV inhibitor, an effective amount of a PYY analog of SEQ ID NO: 12 and an incretin or a DPP-IV inhibitor, or an effective amount of a PYY analog of SEQ ID NO: 13 and an incretin or a DPP-IV inhibitor.

[0081] In those instances in which the incretin is GLP-l or a GLP-l analog, it can be GLP-l or a GLP-l analog such as albiglutide, dulaglutide, liraglutide, semaglutide, or combinations thereof, especially dulaglutide.

[0082] Methods of Making and Using the PYY Analogs

[0083] The PYY analogs herein can be synthesized via any number of peptide synthesis methods known in the art using standard manual or automated solid-phase synthesis procedures. Automated peptide synthesizers are commercially available from, for example, Applied Biosystems (Foster City, CA) and Protein Technologies Inc. (Tucson, AZ). Reagents for solid-phase synthesis are readily available from commercial sources. Solid-phase synthesizers can be used according to the manufacturer's instructions for blocking interfering groups, protecting amino acids during reaction, coupling, deprotecting and capping of unreacted amino acids.

[0084] Typically, an N-a-carbamoyl-protected amino acid and the N-terminal amino acid on the growing peptide chain attached to a resin are coupled at room temperature in an inert solvent such as DMF, N-methylpyrrolidone or methylene chloride in the presence of coupling agents such as diisopropyl -carbodiimide and l-hydroxybenzotriazole. The N-a-carbamoyl protecting group is removed from the resulting peptide resin using a reagent such TFA or piperidine, and the coupling reaction is repeated with the next desired N-a-protected amino acid to be added to the peptide chain. Suitable amine protecting groups are well known in the art and are described, for example, in Green & Wuts,“Protecting Groups in Organic Synthesis,” (John Wiley and Sons, 1991). The most commonly used examples include tBoc and Fmoc. After completion of synthesis, peptides are cleaved from the solid-phase support with simultaneous side chain deprotection using standard treatment methods under acidic conditions.

[0085] One of skill in the art will appreciate that the peptide chains described herein are synthesized with a C-terminal carboxamide. For the synthesis of C-terminal amide peptides, resins incorporating Rink amide MBHA or Rink amide AM linkers typically are used with Fmoc synthesis, while MBHA resin is generally used with tBoc synthesis.

[0086] Crude peptides typically are purified using RP-HPLC on C8 or Cl 8 columns using water-acetonitrile gradients in 0.05 % to 0.1 % TFA. Purity can be verified by analytical RP-HPLC. Identity of peptides can be verified by MS. Peptides can be solubilized in aqueous buffers over a wide pH range.

[0087] One use of the PYY analogs herein is for reducing blood glucose and/or body weight in individuals, especially individuals who are overweight or obese and have T2DM. Administering a PYY analog as described herein can result in glycemic control by improving insulin sensitization and weight loss. As such, the PYY analogs herein show glucose lowering efficacy with the added benefit of weight reduction, such that individuals can delay progression to insulin and maintain target HbAlc goals.

[0088] The methods can include the steps described herein, and these maybe be, but not necessarily, carried out in the sequence as described. Other sequences, however, also are conceivable. Moreover, individual or multiple steps bay be carried out either in parallel and/or overlapping in time and/or individually or in multiply repeated steps. Furthermore, the methods may include additional, unspecified steps.

[0089] Such methods therefore can include selecting an individual who is overweight and has T2DM or is predisposed to the same. Alternatively, the methods can include selecting an individual who is obese and has T2DM or is predisposed to the same.

[0090] The methods also can include administering to the individual an effective amount of at least one PYY analog as described herein, which may be in the form of a pharmaceutical composition as also described herein. In some instances, the at least one PYY analog/pharmaceutical composition can include an additional therapeutic agents such as an incretin or a DPP-IV inhibitor.

[0091] The concentration/dose/dosage of the at least one PYY analog and optional incretin or DPP-IV inhibitor are discussed elsewhere herein.

[0092] With regard to a route of administration, the at least one PYY analog or pharmaceutical composition including the same can be administered in accord with known methods such as, for example, orally; by injection (z.e., intra-arterially, intravenously, intraperitoneally, intracerebrally, intracerebroventricularly, intramuscularly, intraocularly, intraportally or intralesionally); by sustained release systems, or by implantation devices. In certain instances, the at least one PYY analog or pharmaceutical composition including the same can be administered SQ by bolus injection or continuously.

[0093] With regard to a dosing frequency, the at least one PYY analog or pharmaceutical composition including the same can be administered daily, every other day, three times a week, two times a week, one time a week (z.e., weekly), biweekly (z.e., every other week), or monthly. In certain instances, the at least one PYY analog or pharmaceutical composition including the same is administered SQ every other day, SQ three times a week, SQ two times a week, SQ one time a week, SQ every other week or SQ monthly. In particular instances, the at least one PYY analog or pharmaceutical composition including the same is administered SQ one time a week (QW).

[0094] Alternatively, the at least one PYY analog or pharmaceutical composition including the same can be orally administered. As above, and with regard to dosing frequency, the at least one PYY analog or pharmaceutical composition including the same can be administered daily, every other day, three times a week, two times a week, one time a week (z.e., weekly), biweekly (z.e., every other week), or monthly. In certain instances, the at least one PYY analog or pharmaceutical composition including the same is administered orally every other day, orally three times a week, orally two times a week, orally one time a week, or orally every other week. In particular instances, the PYY analog is administered orally one time a week.

[0095] With regard to those instances in which the at least one PYY analog or pharmaceutical composition including the same is administered in combination with an effective amount of an incretin, the incretin can be GCG or a GCG analog, GLP-l, GLP-l (7-36)amide or a GLP-l analog, GIP or a GIP analog, OXM or an OXM analog, GIP/GLP-1, GLP-l/GCG, or even an incretin having triple receptor activity. The GCG, GCG analog, GLP-l, GLP-l (7-36)amide, GLP-l analog, GIP, GIP analog, OXM, OXM analog, GIP/GLP-1, GLP-l/GCG, or incretin having triple receptor activity can be administered simultaneously, separately or sequentially with the at least one PYY analog or pharmaceutical composition including the same.

[0096] Moreover, the GCG, GCG analog, GLP-l, GLP-l (7-36)amide, GLP-l analog, GIP, GIP analog, OXM, OXM analog, GIP/GLP-l, GLP-l/GCG, or incretin having triple receptor activity can be administered with a frequency same as the at least one PYY analog or pharmaceutical composition including the same (i.e., every other day, twice a week, or even weekly). Alternatively, the GCG, GCG analog, GLP-l, GLP-l (7-36)amide, GLP-l analog, GIP, GIP analog, OXM, OXM analog, GIP/GLP-l, GLP-l/GCG, or incretin having

triple receptor activity can be administered with a frequency distinct from the at least one PYY analog or pharmaceutical composition including the same. In other instances, the GCG, GCG analog, GLP-l, GLP-l (7-36)amide, GLP-l analog, GIP, GIP analog, OXM, OXM analog, GIP/GLP-l, GLP-l/GCG, or incretin having triple receptor activity is administered QW. In still other instances, the PYY analog is administered SQ, and the GCG, GCG analog, GLP-l, GLP-l (7-36)amide, GLP-l analog, GIP, GIP analog, OXM, OXM analog, GIP/GLP-l, GLP-l/GCG, or incretin having triple receptor activity can be administered orally.

[0097] It is further contemplated that the methods may be combined with diet and exercise and/or may be combined with additional therapeutic agents other than those discussed above.

EXAMPLES

[0098] The following non-limiting examples are offered for purposes of illustration, not limitation.

[0099] Example 1 : PYY Analog 1.

[0100] One PYY analog incorporating the inventive concept can have a structure of:

[0101] Here, the N-terminus is free, and the C-terminal amino acid is amidated as a C-terminal primary amide. The K at position 7 is chemically modified through conjugation to the e-amino group of the K side chain at position 7 with (Ahx-E-(yE)-CO-(CH2)i6-COOH.

[0102] The PYY analog according to SEQ ID NO:9 is generated by solid-phase peptide synthesis using Fmoc/t-Bu strategy on a SymphonyX Automated Peptide Synthesizer (PTI

Protein Technologies Inc.) starting from RAPP AM-Rink Amide resin (H40023 Polystyrene AM RAM, Rapp polymere GmbH). Amino acid couplings are performed using 10 equivalents of amino acid, 0.9 M diisopropylcarbodiimide (DIC) and 0.9 M Oxyma (1 : 1 : 1 molar ratio) in DMF for 3h at 25°C. Deprotections are carried out using 25% piperidine solutions in DMF.

[0103] After elongating the peptide-resin as described above, the MTT protecting group present in K at position 7 is removed using 30% Hexafluoroisopropanol (HFIP) in dichloromethane (DCM). Additional coupling/deprotection cycles using a Fmoc/t-Bu strategy to extend the K at position 7 side chain involve Fmoc-6-aminohexanoic acid (Chem-Impex International Catalog#02490), Fmoc-Glu(OtBu)-OH, Fmoc-Glu(OH)-OtBu (ChemPep Catalog #100703) and HOOC-(CH2)i6-COOtBu. In all couplings, 3 equivalents of the building block are used with PyBOP (3 equiv) and DIEA (6 equiv) in DMF for 3 h at 25 °C.

[0104] Concomitant cleavage from the resin and side chain protecting group removal are carried out in a solution containing TFA : triisopropylsilane : l,2-ethanedithiol : methanol : thioanisole 80:5:5:5:5 (v/v) for 2 h at 25°C followed by precipitation with cold ether. Crude peptide is purified to >99% purity (15-20% purified yield) by RP-HPLC on a Phenyl Hexyl Column (Phenomenex, Luna; 5 pm, 100 A), where suitable fractions are pooled and lyophilized.

[0105] The purity of the PYY analog is examined by analytical RP-HPLC, and identity is confirmed using LC/MS (observed: M+3H+/3 = 1659.2 (+/-0.2); calculated: M+3H+/3 = 1659.2; observed: M+4H+/4 = 1244.6 (+/-0.2); calculated: M+4H+/4 = 1244.6; observed: M+5H+/5 = 995.9 (+/-0.2); calculated: M+5H+/5 = 995.9).

[0106] Example 2: PYY Analog 2.

[0107] One PPY analog incorporating the inventive concept can have a structure of:

(SEQ ID NO: 10).

[0108] As in Example 1, the N-terminus is free, and the C-terminal amino acid is amidated as a C-terminal primary amide. In contrast, however, the K at position 7 is chemically modified through conjugation to the e-amino group of the K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(yE)-CO-(CH2)ix-COOH.

[0109] The PYY analog according to SEQ ID NO: 10 is generated by solid-phase peptide, similar to that described above in Example 1. Thus, FMOC-NHPEG2-CH2COOH and HOOC-(CH2)i8-COOtBu is attached to the side chain after MTT cleavage using 3 equivalents of the building block with PyBOP (3 equiv) and DIEA (6 equiv) in DMF for 3 h at 25°C.

[0110] The purity of the PYY analog is examined by analytical RP-HPLC, and identity is confirmed using LC/MS (observed: M+3FE/3 = 1665.4 (+/-0.2); calculated: M+3FE/3 = 1665.5; observed: M+4H74 = 1249.3 (+/-0.2); calculated M+4H74 = 1249.4; observed: M+5H75 = 999.7 (+/-0.2); calculated: M+5H75 = 999.7).

CLAIMS

The invention claimed is:

1. A Peptide Tyrosine-Tyrosine (PYY) analog comprising an amino acid sequence of:

PKPEX7PX9X10DASPEEX17X18RYYX22X23LRHYLNX30LTRQRY (Formula I), wherein X7 is any amino acid with a functional group available for conjugation and the functional group is conjugated to a C16-C22 fatty acid,

wherein X9 is E or G,

wherein Xl0 is E or K,

wherein X17 is L or W,

wherein Xl8 is N or Q,

wherein X22 is A or I,

wherein X23 is E, D or S,

wherein X30 is E or W (SEQ ID NO:3), and

wherein a C-terminal amino acid is optionally ami dated.

2. The PYY analog of Claim 1, wherein X7 is selected from the group consisting of C,

D, E, K and Q.

3. The PYY analog of Claim 1, wherein X7 is K and conjugation to the C16-C22 fatty acid is through an epsilon-amino group of a K side chain.

4. The PYY analog of Claim 1, wherein the amino acid sequence is selected from the group consisting of:

PKPEKPGED ASPEEW QRYY AELRHYLNWLTRQRY (SEQ ID NO:4);

PKPEKPGED ASPEEW QRYY AELRHYLNELTRQRY (SEQ ID NO: 5);

PKPEKPEED ASPEEW QRYYIELRHYLNWLTRQRY (SEQ ID NO: 6);

PKPEKPGKD ASPEEWNRYY ADLRHYLNWLTRQRY (SEQ ID NO: 7); and

PKPEKPGED ASPEELQRYYASLRHYLNWLTRQRY (SEQ ID NO: 8).

5. The PYY analog of any one of Claims 1 to 4, wherein the C16-C22 fatty acid is selected from the group consisting of a hexadecanoic acid, a hexadecanedioic acid, a heptadecanoic acid, a heptadecanedioic acid, a stearic acid, an octadecanedioic acid, a nonadecylic acid, a nonadecanedioic acid, an eicosanoic acid, an eicosanedioic acid, a heneicosanoic acid, a heneicosanedioic acid, a docosanoic acid, a docosanedioic acid, and branched and substituted derivatives thereof.

6. The PYY analog of Claim 5, wherein the C16-C22 fatty acid is a C18-C20 fatty acid.

7. The PYY analog of Claim 6, wherein the C18-C20 fatty acid is a straight-chain fatty acid having a formula of C0-(CH2)X-C02H, and wherein x is 18 or 20.

8. The PYY analog of Claim 7, wherein the C18-C20 fatty acid is selected from the group consisting of palmitic acid, stearic acid, arachidic acid and eicosanoic acid.

9. The PYY analog of any one of Claims 1 to 8, wherein the C16-C22 fatty acid is conjugated to the amino acid with the functional group available for conjugation via a linker.

10. The PYY analog of Claim 9, wherein the linker can be one or more units selected from the group consisting of [2-(2-amino-ethoxy)-ethoxy)]-acetic acid (AEEA), aminohexanoic acid (Ahx), glutamic acid (E), gamma glutamic acid (gE) and combinations thereof.

11. A Peptide Tyrosine-Tyrosine (PYY) analog comprising:

(SEQ ID NO:9).

12. A Peptide Tyrosine-Tyrosine (PYY) analog comprising:

14. A Peptide Tyrosine-Tyrosine (PYY) analog comprising:

(SEQ ID NO: 12).

15. A Peptide Tyrosine-Tyrosine (PYY) analog comprising:

(SEQ ID NO: 13).

16. The PYY analog of any one of Claims 1 to 15, wherein the PYY analog has a charge of greater than -2.

17. The PYY analog of any one of Claims 1 to 16, wherein the PYY analog has a binding affinity at a NPY2 receptor that is greater than that of PYY3-36 (SEQ ID NO:2).

18. The PYY analog of any one of Claims 1 to 17, wherein the PYY analog has a half-life that is greater than that of human PYY3-36 (SEQ ID NO:2).

19. A pharmaceutical composition comprising:

at least one Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a salt thereof; and

one or more pharmaceutically acceptable carriers, diluents and excipients.

20. The pharmaceutical composition of Claim 19 further comprising an additional therapeutic agent.

21. The pharmaceutical composition of Claim 20, wherein the additional therapeutic agent is an incretin selected from the group consisting of glucagon (GCG), a GCG analog, glucagon-like peptide- 1 (GLP-l), GLP-l 7-36-amide, a GLP-l analog, gastric inhibitory peptide (GIP), a GIP analog, oxyntomodulin (OXM), an OXM analog, a GIP/GLP-l, a GLP-l/GCG, or an incretin analog having triple receptor activity.

22. The pharmaceutical composition of Claim 20, wherein the additional therapeutic agent is a dipeptidyl peptidase-IV (DPP-IV) inhibitor.

23. A method of treating obesity or an obesity related disease or disorder, the method comprising a step of:

administering to an individual in need thereof an effective amount of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof.

24. The method of Claim 23, wherein the PYY analog or pharmaceutically acceptable salt thereof is subcutaneously (SQ) administered to the individual.

25. The method of Claim 23, where the PYY analog or pharmaceutically acceptable salt thereof is orally administered to the individual.

26. The method of Claim 24 or 25, wherein the PYY analog or pharmaceutically acceptable salt thereof is administered daily, every other day, three times a week, two times a week, one time a week, or biweekly.

27. The method of Claim 23, wherein the PYY analog or pharmaceutically acceptable salt thereof is administered SQ one time a week (QW).

28. The method of Claim 23, wherein the PYY analog or pharmaceutically acceptable salt thereof is administered orally one time a week.

29. The method of any one of Claims 23 to 28 further comprising administering an additional therapeutic agent.

30. The method of Claim 29, wherein the additional therapeutic agent is an incretin selected from the group consisting of glucagon (GCG), a GCG analog, glucagon-like peptide- 1 (GLP-l), GLP-l 7-36-amide, a GLP-l analog, gastric inhibitory peptide (GIP), a GIP analog, oxyntomodulin (OXM), an OXM analog, a GIP/GLP-l, a GLP-l/GCG, or an incretin analog having triple receptor activity.

31. The method of Claim 29, wherein the additional therapeutic agent is a dipeptidyl peptidase-IV (DPP-IV) inhibitor.

32. Use of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof for treating obesity.

33. Use of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof for treating an obesity-related disease or disorder.

34. Use of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof for treating type II diabetes mellitus.

35. Use of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating obesity.

36. Use of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating an obesity-related disease or disorder.

37. Use of a Peptide Tyrosine-Tyrosine (PYY) analog of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating type II diabetes mellitus.