EXTRACTED FROM WIPO SITE
NOVEL ANALOGUES RELATED APPLICATIONS This application claims the benefit of three Indian provisional applications having application IN 201821013109 on April IN 201821040468 on October and IN 201821040474 on October which are hereby incorporated by FIELD OF THE DISCLOSURE The present disclosure relates to novel Glucagon like 1 analogs having an amino acid sequence with Leu or lie at the The new analogs are potent agonists with reduced adverse effect and improved duration of The present disclosure further relates to acylated derivatives of the new which have further improved potency and duration of action and are suitable for oral The analogs disclosed herein are acylated with protracting which increase the duration of activity of the The analogs disclosed herein may be useful in treatment of diabetes and BACKGROUND OF THE DISCLOSURE is a hormone that is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing protein hydrolysate glucose enters the duodenum is derived from the processing of the preproglucagon the peptide was identified from this but it was the two truncated ID and that were found to recognize the pancreatic receptor and which were determined to be the active species in has been found to stimulate insulin thereby causing glucose uptake by cells and decreased serum glucose agonists are available for the treatment for Type 2 Diabetes Mellitus as favored drugs as they are devoid of hypoglycemia and with a positive benefit of weight The endogenous and are cleaved by peptidases and thus have a very short Efforts were made to improve the performance by developing analogues with improved The first drug approved in 2005 was Exenatide with twice a day dosing at dose level 10 meg and was found to show a significant improvement in a marker of glucose Novo Nordisk developed Liraglutide States Patent ID with once a day dosing of and approved in Further research and development produced once a week products Albiglutide developed by GSK and Dulaglutide developed by Eli Semaglutide Publication WO a analogue was approved by Semaglutide ID is marketed under the brand name It is administered as a subcutaneous Many attempts to make analogs having improved potency and duration of action are reported in United States Patent B2 discloses derivatives having added several residues of arginine lysine to the terminus thereof to provide high bioavailability via mucous membranes The 594 patent further discloses that these derivative can be conferred with resistance to dipeptidyl peptidase IV by substituting amino acid 8 in its amino acid sequence with or with resistance to trypsin by substituting amino acids 26 and 34 with Gln and United States Patent B2 discloses acylated analog wherein the analog is stabilized against by modification of at least one amino acid residue in positions 7 and 8 relative to the sequence and wherein said acylation is a diacid attached directly to the amino acid residue of said United States Patent B2 discloses a resistant analogue having a amino acid residue containing trifluromethyl group in position 8 relative to the sequence and is acylated with a moiety comprising two acidic groups to the lysine residue in position United States Patent B2 US discloses analogues having Val or Gly at position 8 relative to the sequence as resistant International Publication WO WO discloses analogues having a Trp at a position corresponding to position 8 of and these Trp8 compounds were shown to be very stable against degradation by International Publication WO WO discloses that the modification at the position to 9 position in case of can produce analogues with greatly reduced susceptibility to as cleavage relative to the native yet retain the biological activity of the native The further discloses analogues having an amino acid with carbon as at position 9 provides analogues with resistant to degradation by International Publication WO A2 discloses that incorporation of amino acids directly into the main chain of analogues has been determined to produce Various other resistant agonists are disclosed in patent publications such as International Publication WO WO WO WO WO WO WO Al and WO Various patent applications disclose extended analogues with increased stability and longer duration of For United States Patent B2 and Various patent applications disclose acylated analogs wherein the analogues are attached to lipophilic substituent optionally via a linker to provide longer duration of United States Patent B2 discloses monoacylated derivatives of analogues wherein Lys residue at position 37 or 38 of analogue is United States Patent 178 B2 and United States Patent Application Publication US US Al disclose derivatives of United States Patent Application Publication US Al discloses triacylated derivatives of International Publication WO WO Al and WO Al disclose acylated analogues wherein the Uys residue of analogues is attached to two protracting moieties via a branched International Publication WO Al and WO Al disclose various acylating agents which can be attached to Uys residue of analogues to provide longer duration of International Publication WO A2 discloses peptide analogues having Ser or functionalized Ser or functionalized or at position 2 of amino acid Various other analogues are disclosed in patent applications such as International Publication WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO WO A 1 and WO there is need to develop analogs which have optimum desired properties in terms of stability and duration of SUMMARY OF THE DISCLOSURE One aspect the present disclosure provides a polypeptide comprising the amino acid wherein X2 is Ala or X3 is absent or X4 is X16 is X24 is X33 is or X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U is absent or wherein is point of attachment with group W is absent or selected from a group consisting and wherein is point of attachment with group Y Y is point of attachment with the group Z is or wherein n is an integer from 14 to The polypeptides of the present disclosure are potent agonists with fewer adverse the polypeptides of the present disclosure are stable and have long duration of action and are suitable for oral DESCRIPTION OF FIGURES Figure 1A illustrates the preparation of Moiety Figure 1B illustrates the preparation of Moiety Figure 2 illustrates the preparation of Moiety Figure 3 illustrates the preparation of Moiety Figure 4 illustrates the preparation of Moiety Figure 5 illustrates the preparation of Moiety Figures 6A and 6B illustrate the results of an oral glucose tolerance test for Compound 1 in single glucose AUC 22 Fig 46 Figure 7 illustrates the reduction in blood glucose levels in type 2 diabetic mice after chronic treatment with Compound Figure 8 illustrates the reduction in food intake in mice following treatment with Compound Figure 9 illustrates the efficacy of Compound 1 in mice in reduction of body Figure 10 illustrates the reduction in HblAc in mice following treatment with Compound ABBREVIATIONS acid acid Oral glucose tolerance test DIPC IBCF Isobutyl chloroformate morpholine Tetrahydrofuran Dichloromethane Dicyclohexyl carbodiimide Dimethylacetamide DESCRIPTION OF THE DISCLOSURE The present disclosure provides a stable long acting which does not require frequent subcutaneous dosing and is also suitable for oral It was surprisingly found that the addition of an extra Leu at the C terminal of the sequence produced peptides with significantly improved potency and duration of action when compared to the parent The peptides with an extra Ile also showed similar effect of improved potency and duration of action when compared to the parent the disclosure herein demonstrates which can be appended to peptides which are analogs of via acylation reaction to produce compounds with significantly improved potency and longer duration of The protracting moieties of the disclosed compounds have more stable which are less susceptible to cleavage by biological the compounds disclosed herein are more stable and require less frequent administration adding to patient in some the disclosure provides a polypeptide comprising the amino acid ID wherein X2 is Ala or X3 is absent or X4 is X16 is X24 is X33 is or X34 is absent and X21 is Lys wherein the side chain amino group of Lys is In some X21 can be acylated with the protracting moieties reported in United States Patent 178 B2 and United States Patent Application Publication US Al and US International Publication WO WO A2 and WO Al In some the X21 Lys is acylated at its side chain amino group with a moiety comprising a fatty acid The fatty acid group may be attached to X21 Lys via a in some the present disclosure provides a polypeptide comprising the amino acid wherein X2 is Ala or Aib X3 is absent or X4 is X16 is X24 is X33 is or X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U is absent or wherein is point of attachment with group W is absent or selected from a group consisting and wherein is point of attachment with group Y Y is point of attachment with the group Z is or wherein n is an integer from 14 to In some the amino acid at X2 is selected from Ala or In some embodiments X2 is In some X3 is In some X33 is In some X33 is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is selected from a group consisting In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein U and W both are absent and Z is wherein n is an integer In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Z is wherein n is integer In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Z is wherein n is an integer In some X2 is Ala or X3 is X33 is U is W is Y is is point of attachment with the group Z is wherein n is integer In some the present disclosure provides a polypeptide comprising the amino acid wherein X2 is X3 is X4 is X16 is X24 is X33 is X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U wherein is point of attachment with group W is wherein is point of attachment of group Y is point of attachment with the group Z is wherein n is integer In some the present disclosure provides a polypeptide comprising the amino acid wherein X2 is Aib X3 is X4 is X16 is X24 is X33 is X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U is wherein is point of attachment with group W is wherein is point of attachment with group Y is point of attachment with the group Z is wherein n is integer In some the present disclosure provides a polypeptide comprising the amino acid wherein X2 is X3 is X4 is X16 is X24 is X33 is X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U wherein is point of attachment with group W is wherein is point of attachment with group Y Y is point of attachment with the group Z is wherein n is integer In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some the disclosure provides a polypeptide comprising the amino acid wherein X2 is X3 is X4 is X16 is X24 is X33 is X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U wherein is point of attachment with group W is wherein is point of attachment of group Y Y is is point of attachment with the group Z is or wherein n is an integer from 14 to In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Z is wherein n is integer In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Z is wherein n is integer In some the present disclosure provides a polypeptide comprising the amino acid wherein X2 is X3 is X4 is X16 is X24 is X33 is X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U is wherein is point of attachment with group wherein is point of attachment with group Y Y is is point of attachment with the group and Z is wherein n is integer In some the present disclosure provides a polypeptide comprising the amino acid wherein X2 is X3 is X4 is X16 is X24 is X33 is X34 is absent and X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein Q and T are U is wherein is point of attachment with group W is wherein is point of attachment with group Y Y is is point of attachment with the group and Z is or wherein n is an integer from 14 to In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is Lys wherein the side chain amino group of Lys is acylated with a wherein W is In some X21 is lipid modified Lys wherein the side chain amino group of Lys is acylated with a moiety which is represented by the moieties provided in Table 1 Table Representative moieties for group Designation Moiety In another the present disclosure provides a polypeptide according to any one of the preceding which is selected from the peptides provided in Table Table Representative polypeptide compounds of present disclosure Unless stated all the amino acids in the structures have L configuration at a D when used as a prefix to amino acid in the sequence denotes the D configuration of the amino For example denotes that Serine amino acid in the sequence has Unless stated the disclosure intends to cover both L and D isomers of the amino acids in the as described herein in the disclosure is amino acid serine with its hydroxyl group methylated and has following The polypeptide sequences mentioned in the disclosure are represented by the single letter code of the amino acids as approved by Y and Z as used herein to define the acylating moiety of the embodiments of the present disclosure are different than the single letter code of the amino acid used to denote the polypeptide The polypeptides of the present disclosure surprisingly showed significant reduction in the blood glucose when subjected to an oral glucose tolerance test in SD The percentage reduction of blood glucose in SD rats when challenged with oral glucose was significantly lower than the corresponding polypeptides which lacked the additional Leu or lie at X33 The present invention is further illustrated in detail with reference to the following It is desired that the example be considered in all respect as illustrative and are not intended to limit the scope of the claimed General Methods of The polypeptide compound of the present disclosure can be prepared by methods described herein The process involves two involving preparation of the parent linear peptide and subsequent attachment of fatty acid chain to the parent The peptides described herein may be prepared by chemical synthesis using techniques such as those described in Barany and Volume Methods in Peptide Part Gross and Academic New and in Stewart and Peptide 2nd Pierce Chemical The desired strategy is based on the Fmoc group for temporary protection of the in combination with protecting groups such as butyl trityl groups for temporary protection of the amino acid side chains for example Atherton and Fluorenylmethoxycarbonyl Amino Protecting Volume Methods in Peptide Part Undenfriend and Academic San The peptides can be synthesized in a stepwise manner on an insoluble polymer support referred to starting from the of the A synthesis is begun by appending the amino acid of the peptide to the resin through formation of an amide or ester This allows the eventual release of the resulting peptide as a terminal amide or carboxylic The amino acid and all other amino acids used in the synthesis are required to have their groups and side chain functionalities differentially protected such that the protecting group may be selectively removed during the The coupling of an amino acid is performed by activation of its carboxyl group as an active ester and reaction thereof with the unblocked group of the amino acid appended to the The sequence of group deprotection and coupling is repeated until the entire peptide sequence is The peptide is then released from the resin with concomitant deprotection of the side chain usually in the presence of appropriate scavengers to limit side The resulting peptide is finally purified by reverse phase The parent peptide can then be coupled to the fatty acid chain by coupling the activated fatty acid chain with the parent peptide The fatty acid chain may be made by methods well known in organic For the fatty acid chain can be made using solid phase synthetic methods which enables preparation of linear fatty acid The linear peptides synthesized were purified by preparative HPLC procedure as outlined Preparative WATERS 2555 Quaternary gradient module Total 300 Max 3000 or Shimadzu Total 150 Max 20 Cl 10m 75 Mobile For first purification Mobile Phase pH Phosphate buffer Mobile Phase Acetonitrile 10 to Mobile in 300 For second Mobile Phase Acetic acid in water Mobile Phase Acetic acid in 15 to Mobile in 300min The final compounds of the present disclosure were purified by preparative HPLC procedure as outlined Preparative WATERS 2555 Quaternary gradient module Total 300 Max 3000 or Shimadzu Total 150 Max 20 Cl 10m Mobile The purity of the compounds of the present disclosure was analysed by method as outlined HPLC Method YMC mm X 150 mm Mobile Phase Trifluroacetic acid in Water Mobile phase Trifluroacetic acid in Acetonitrile Flow UV detection at 210 nm Column 50 Run 50 HPLC Method Pro C18 mm x 250 Mobile Phase Acetonitrile Mobile phase Acetonitrile Potassium dihydrogen orthophosphate in pH adjusted to l with orthophosphoric acid Flow l UV detection at 210 nm Column 50 Sample Tray 8 Run 38 HPLC Method Waters X Mobile Phase Acetonitrile Mobile phase Acetonitrile Potassium dihydrogen orthophosphate in pH adjusted to l l with orthophosphoric acid Flow UV detection at 210 nm Column 40 Sample Tray 5 Run 100 The compounds of the present disclosure were analyzed by the LCMS as outlined Mass spectra were recorded on LCMS using Waters Waters Micromass Quattro Micro API or Thermo scientific LCQ The test solution was prepared by dissolving a suitable quantity of analyte in diluent with a final concentration from 1 to depending on the ionization of The test solution was infused at a rate of about 10 to 50 per minute into LCMS for 1 min and mass spectra were recorded in Electro Spray Ionization positive or negative mode and in an appropriate mass Example Preparation of activated fatty acid side Preparation of acid The activated fatty acid side Moiety was prepared by solid phase synthesis using chloride resin as schematically represented in Figure acetic acid was attached to chloride resin in presence of which yielded acetic The lean be prepared by coupling of acetic acid with Fmoc is available commercially and can be procured as The Fmoc protecting group was removed by selective of amino group of acetic using piperidine and the free amino group was then coupled to acid using and which yielded acetic The Fmoc group was then removed by selective of amino group of acetic using piperidine and the free amino group was then coupled to OtBu using HOBt and DIPC to obtain acetic The resultant pentanoy acetic was selectively deblocked using piperidine and then coupled with octadecanedioic acid mono ester to give namely acetic The intermediate 2 was then cleaved from using trifluoroethanokDCM The resultant compound was then reacted with hydroxysuccinimide in presence of isobutyl chloroformate and methylmorpholine followed by with trifluoroacetic acid to yield the title compound The whole process can also be depicted as schematically represented in Figure Preparation of succinimide ester Moiety acid ester was reacted with palmitic acid in presence of IBCF and NMM to yield which was then reacted with HOSu in the presence of IBCF and NMM to yield which was then with trifluoroacetic acid to yield Moiety Preparation of octadecanoic acid The activated fatty acid side Moiety was prepared using solid phase synthesis using chloride resin as schematically represented in Figure acid was attached to chloride resin in presence of DIPEA to yield The Fmoc protecting group was removed by selective of amino group using piperidine and the free amino group was then activated using reform ate in THF and DIPEA followed by reaction with butylamine hydrochloride salt in DMAc and which yielded acetic The Fmoc group was removed by selective using piperidine and the free amino group was then coupled to using of HOBt and which yielded acetic The resultant was selectively deblocked using piperidine and then coupled with octadecanedioic acid mono ester to give intermediate The intermediate was then cleaved from using trifluoroethanokDCM to obtain acetic acid The resultant compound was then reacted with HOSu in presence of dicyclohexyl carbodiimide to yield succinimide protected which was with trifluoroacetic acid to yield the title compound Preparation of acid The fatty acid side chain was prepared using solid phase synthesis using chloride resin as schematically represented in Figure acid was attached to chloride resin in presence of DIPEA to yield The Fmoc protecting group was removed by selective of amino group using piperidine followed by coupling with in DMAc using DIPC and HOBt which yielded The Fmoc group was removed by selective using piperidine and the free amino group was coupled with using HOBt and DIPC to yield acetic The Fmoc group of the resultant compound was selectively using piperidine and the free amino group was then coupled with octadecanedioic acid mono tert butyl ester to give methyl acetic The intermediate was then cleaved from using trifluoroethanokDCM to obtain acid The resultant compound was then reacted with HOSu in presence of DCC to yield succinimide protected which was with trifluoroacetic acid to yield the title compound Preparation of octadecanoic acid The fatty acid side chain was prepared using solid phase synthesis using chloride resin as schematically represented in Figure acid was attached to chloride resin in presence of DIPEA to yield The Fmoc protecting group was removed by selective of amino group using piperidine and the free amino group was then activated using in THF and DIPEA followed by reaction with in DMAc in presence of DIPEA using HOBt to form The free amino group was then coupled to using HOBt and which yielded acetic The resultant was selectively deblocked using piperidine and then coupled with octadecanedioic acid mono tert butyl ester to give The intermediate was then cleaved from using trifluoroethanokDCM to obtain acetic acid The resultant compound was then reacted with HOSu in presence of dicyclohexyl carbodiimide to yield succinimide protected which was with trifluoroacetic acid to yield the title compound Preparation of octadecanoic acid The fatty acid side chain was prepared using solid phase synthesis using chloride resin as schematically represented in Figure acid was attached to chloride resin in presence of DIPEA to yield The Fmoc protecting group was removed by selective of amino group using piperidine and the free amino group was then activated using in THF and DIPEA followed by reaction with in DMAc in presence of DIPEA using HOBt which yielded acetic acid The resultant compound on cleavage using trifluoro acetic acid yielded acid which on further reaction with in presence of triethylamine yielded The obtained compound was then further attached to chloride resin in presence of DIPEA to yield Fmoc group was removed by selective using piperidine and the free amino group was then coupled with using HOBt and which yielded acetic The resultant compound was selectively using piperidine and was then coupled with octadecanedioic acid mono ester to give Intermediate was then cleaved from using trifluoroethanokDCM to acid The resultant compound was then reacted with HOSu in presence of DCC to yield succinimide protected which was using trifluoroacetic acid to yield the title Moiety Example Synthesis of Compound Leu38 peptide Part Synthesis of the parent linear peptide Leu38 The parent peptide was synthesized by The starting resin used for synthesis was Wang Fmoc protected Leucine was used for coupling with the Wang The coupling was performed by using hydroxybenzotriazole as coupling reagent in presence of dimethylaminopyridine which yielded Selective de blocking of amino group of Resin using piperidine followed by coupling with using HOBt and DIPC yielded This completes one Acetic anhydride and diisopropylethyl was used to terminate the uncoupled amino groups at every amino acid The above 2 selective deblocking of protection of amino acid attached to the resin and coupling of next amino acid residue in sequence with amino group were repeated for remaining 30 amino acid The selective deprotection of Fmoc group was done using piperidine and coupling with next Fmoc protected amino acid was done using The side chain of the amino acids were protected hydroxyl group of Tyrosine or Threonine were protected with amino and guanido group of Lysine and Arginine were protected with and group the imidazole of histidine was protected with trityl and carboxylic acid groups of aspartic acid or glutamic acid were protected with The above mentioned two selective deblocking and then coupling with next Fmoc protected amino acid were performed to get of using piperidine followed by cleavage and using trifluoroacetic acid with resulted in crude Leu38 which was purified by Part Grafting of activated fatty acid Moiety over purified obtained in Part in acetonitrile at pH about 10 resulted in crude title peptide which was purified by preparative The characterization of the compounds is provided in Table Example Preparation of Compound and 12 The linear peptides of the compounds 10 and 12 were prepared by solid phase method as per the analogous process given for Example 1 Part Grafting of activated fatty acid Moiety by following the process of Example Part B over the respective linear peptides afforded compound 10 and Example Preparation of Compound 4 and The linear peptides of the Compound 4 and 11 were prepared by solid phase method as per the analogous process given for Example Part A except here Fmoc protected was first coupled with Wang resin and then sequentially other amino acids were Grafting of activated fatty acid Moiety over the respective linear peptide by following the process of Example Part B afforded the Compound 4 and Example Preparation of Compound 8 The linear peptide was prepared by solid phase method as per the analogous process given for Example Part A except here Fmoc protected Isoleucine was first coupled with Wang resin and then sequentially other amino acids were The grafting of activated fatty acid Moiety over the linear peptide by following the process of Example Part B afforded the Compound Example Preparation of Compound 6 The linear peptide was prepared by solid phase method as per the analogous process given for Example Part The grafting of activated fatty acid Moiety over the linear peptide by following analogous process of Example Part B afforded the Compound 6 Example Preparation of Compound 7 The grafting of activated fatty acid Moiety over the linear peptide of the Example Part by following analogous process of Example Part B afforded the Compound Example Preparation of Compound 13 The grafting of activated fatty acid Moiety over the linear peptide of the Example Part by following analogous process of Example Part B afforded the Compound Example Preparation of Compound 14 The linear peptide was prepared by solid phase method as per the analogous process given for Example Part The grafting of activated fatty acid Moiety over the linear peptide by following analogous process of Example Part B afforded the Compound Example Preparation of Compound 15 The linear peptide was prepared by solid phase method as per the analogous process given for Example Part A starting with Fmoc protected Isoleucine was first coupled with Wang resin and then sequentially other amino acids were The grafting of activated fatty acid Moiety over the linear peptide by following analogous process of Example Part B afforded the Compound Example 11 Preparation of Compound 16 The grafting of activated fatty acid Moiety over the linear peptide of the Example Part by following analogous process of Example Part B afforded the Compound Example Preparation of Compound 17 The grafting of activated fatty acid Moiety over the linear peptide of the Example Part A by following analogous process of Example Part B afforded the Compound Example Preparation of Compound 18 The grafting of activated fatty acid Moiety over the linear peptide of the Example Part by following analogous process of Example Part B afforded the Compound The characterization data of the synthesized compounds of the present disclosure are provided below in following Table Table Characterization data of representative compounds of the present disclosure Example Oral Glucose tolerance test in Single Animals were divided into three groups a normal control a test group and a third semaglutide with 4 animals in each The animals were fasted for 12 hours before initiation of To the test group the Compound 1 was injected subcutaneously at 1 To the semaglutide a dose of 1 was injected After 22 166 hrs and 334 hrs of subcutaneous injection of test drug or blood glucose was measured with blood glucose meter 0 All the animals were then given 2 of glucose solution Blood glucose was measured at 90 and 120 minutes following glucose Body weight and food intake was Blood glucose data was analyzed using Two way ANOVA followed by Bonferroni posttests using PRISM Pad version Data of Blood glucose was analyzed using t The polypeptides of the present disclosure have shown significant glucose lowering effect compared to the control group when studied in Oral Glucose Tolerance Test in For Figure 6 provides change in blood glucose level from time 0 to 120 min after 22 hrs and 46 hrs in the test group administered Compound 1 and the semaglutide treatment At 22 hours after single the Compound 1 showed statistically significant reduction in blood glucose level with vs normal control in ANOVA followed by The glucose lowering effect of the Compound 1 was superior to the glucose lowering effect observed with semaglutide see Figure The superiority of glucose lowering effect of the Compound 1 was observed even after 46 hours of subcutaneous administration both the Compound 1 and semaglutide showed statistically significant reduction in food intake as compared to control when observed on day 2 as well as on day 4 see Table 4 The reduced food intake shown by Compound 1 on day 4 was greater than semaglutide Table In terms of body weight only the test compound showed significant reduction on body weight on day Table Effect of treatment on food intake and body weight on Day 2 vs Normal one way ANOVA followed by posttests Table 5 Effect of treatment on food intake and body weight on Day 4 vs Normal one way ANOVA followed by posttests vs one way ANOVA followed by posttests It was surprisingly found that compounds having X33 as Leu and Ile showed significant reduction of the blood glucose in the given studies whereas compounds with amino acids other than Leu and had significantly less effect in lowering the blood The polypeptide of present disclosure has shown significant reduction in blood glucose when compared to the control Compounds having amino acids other than Leu or at X33 positions were also For Leu at 32nd position in Compound 1 ID was replaced with Lys and Ser to obtain compounds and 1 and showed only about 35 and 15 reduction in blood glucose Table Percentage reduction in Blood Glucose in OGTT test 1 dose after 24 the compound 6 which differs from liraglutide in having an additional Leu at 32nd position and the compound 7 which differs from liraglutide by having 2nd amino acid Ala replaced with Aib and having Leu as an additional 32nd amino showed blood glucose lowering effect at 24 hrs which was significantly higher than liraglutide Once it was determined that the Compound 1 was significantly better in terms of glucose food intake and body weight experiments were conducted to determine the duration of action of the compound of the present The effect of the representative compounds of the present invention 13 and after 166 hrs and 334 hrs was studied and compared with that of The compounds were tested as per the method provided Animals were divided into three groups a normal control a test group and a third semaglutide with 4 animals in each The animals were fasted for 12 hours before initiation of To the test group Compound Compound 13 and Compound 16 were injected subcutaneously at 1 To the semaglutide a dose of 1 was injected After 22 166 hrs and 334 hrs of subcutaneous injection of test compound or blood glucose was measured with blood glucose meter 0 All the animals were then given 2 of glucose solution Blood glucose was measured at 90 and 120 minutes following glucose Body weight and food intake was Blood glucose data was analyzed using Two way ANOVA followed by Bonferroni posttests using PRISM Pad version Data of Blood glucose AU 120 was analyzed using t Table 7 provides the reduction in AUC of blood glucose for the representative compounds of present invention 13 and in comparison with the control group after 1 7 days and 14 days of Table Percentage reduction in Blood Glucose in OGTT test 1 Compounds 1 and 13 were studied and compared with semaglutide in one experiment and Compound 16 was studied and compared with semaglutide in a separate experiment After 168 hrs of the Compound 13 and 16 of present invention showed about 60 reduction in blood glucose AUC when compared to time zero blood glucose On the other semaglutide showed just about 25 reduction in blood glucose level with respect to time zero blood glucose Similar observations were made in quantity of food consumed and body weight As can be seen in the Table 8 below the animals administered with the representative compounds 13 and consumed significantly less food when compared to the animals administered with Compound 16 showed substantial lowering of body weight demonstrating potential utility for the treatment of Table Effect on food consumption and body weight in OGTT test 1 dose Example Reduction of HbAlc in type 2 diabetic mice after chronic treatment This study was done in diabetic mouse The animals were divided into three treatment a diabetic control a test group and a semaglutide treatment Compound lof the present disclosure was injected subcutaneously at dose once a day for 3 days followed by dose every alternate day for 7 doses followed by dose once every four days for two dose cycles The same dosage regimen was administered in semaglutide treatment Measurements of blood glucose levels and body weight were done was measured on Day day day 14 and day 27 by column Cumulative food intake was calculated on day data was analyzed by two way ANOVA followed by posttests using PRISM Pad version The test group animals administered with the Compound 1 showed statistically significant reduction in blood glucose levels as compared to the diabetic control group Figure and the effect was superior to semaglutide treatment group in latter phase of the The test group animals administered with Compound 1 showed significant reduction in food intake as can be seen in the results provided in Figure Figure 8 provides cumulative food intake from 0 to 27th day by control and mice treated with the test Both the test compound and semaglutide showed a statistically significant reduction in food intake as compared to the diabetic control the test compound showed a significantly lower food as compared to In the same the Compound 1 has also shown significant reduction in body weight when compared to diabetic control Figure 9 provides the result of change in body weight for control and test group from day 0 to day The test Compound 1 showed a significant reduction of as compared to as observed in semaglutide treatment group Figure In diabetes higher amounts of indicating poorer control of blood glucose have been associated with cardiovascular and In a 27 day Compound 1 showed statistically significant reduction in HbA lc level in type 2 diabetic mice after chronic Table 9 below and Figure 10 provide the level of HbAlc at 0 and 27 days in Diabetic control group and group after chronic treatment with the Compound The effect was statistically significant even when compared to Table Effect of treatment on HbAlc levels in mice vs Diabetic two way ANOVA followed by posttests vs one way ANOVA followed by posttests In a separate test Compound 13 and 16 were studied and compared with semaglutide for their effect on HbAlc insulin level and cumulative food body weight change and blood glucose The study was performed in similar manner as above on diabetic mouse The animals were divided into three treatment groups a diabetic control a test group and a semaglutide treatment The representative compounds of the present Compound Compound 13 and Compound were injected subcutaneously at or nM dose alternate day up to day 28 The same dosage regimen was administered in semaglutide treatment Measurements of blood glucose levels and body weight were done Insulin was measured on Day day 14 and day Cumulative food intake and body weight change was calculated on day 14 and Insulin data was analyzed by two way ANOVA followed by posttests using PRISM Pad version Whereas Blood Glucose Body weight change and Cumulative food intake data was analyzed by one way ANOVA followed by posttests using PRISM Pad version From day 29 to day animals were kept on recovery period during which no drug treatment was Blood Glucose and Body weight was measured during this On day Body weight Insulin was The results are provided in Tables 11 and 12 Table HbAlC Compound 1 Compound 13 Compound 16 Table Insulin Compound 1 Compound 13 Compound 16 Table Cumulative food Blood Glucose and Body Weight Compound 1 Compound 13 Compound 16 vs Diabetic vs One way ANOVA followed by Bonferroni posttests The representative compounds of the present disclosure 13 and at about 3 nM and 6 nM dose showed significant reduction in blood food consumption and body weight when compared to control The reduction was comparable to that shown by semaglutide at about 12 nM the effect was seen even after 29 days 13 and which demonstrates the potential of compounds of present invention for developing long acting drug which do not require frequent administration and hence adding to the patient Table Recovery Glucose AUC Table Recovery and Insulin vs Diabetic Control and vs One Way ANOVA followed by posttests These results demonstrate that the compound of present invention can find potential use for the treatment of diabetes and insufficientOCRQuality

WE CLAIM:
1. A polypeptide comprising the amino acid sequence:
H-X2-X3-X4-G-T-F-T-S-D-V-S-S-Y-L-X16-G-Q-A-A-X21-E-F-X24-A-W-L-V- R-G-R-G-X33-X34
wherein X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib, ;
X3 is absent or Gln;
X4 is Glu;
X16 is Glu;
X24 is He;
X33 is Leu, -D-Leu, D-Ile or He;
X34 is absent and
X21 is Lys wherein the side chain amino (F amino) group of Lys is acylated with a moiety:
{— Q-T— U-W-Y-Z
wherein Q and T are absent;
U is absent or -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-} wherein } is point of attachment with group W;
W is absent or selected from a group consisting of -C(0)-CH2-0-(CH2)2-0-(CH2)2- NH-], -C(0)-NH-(CH2)3-4-NH-], -C(0)-C(CH3)2-NH-] and
wherein ] is point of attachment with group Y ;
Y is-C(0)-(CH2)2-CH(C00H)NH— and— is point of attachment with the group Z;
Z is -C(0)-(CFh)n-C00F[ or -C(0)-(CH2)n-CH3 wherein n is an integer from 14 to 20
2. The polypeptide as in claim 1, wherein X2 is Aib;
X3 is absent;
X33 is Leu;
U is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-};
W is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-] and
Z is -C(0)-(CH2)n-C00H wherein n is integer 16.
3. The polypeptide as in claim 1, wherein X2 is Aib;
X3 is absent;
X33 is Leu;
U is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-};
W is -C(0)-C(CH3)2-NH-] and
Z is -C(0)-(CH2)n-C00H wherein n is integer 16.
4. The polypeptide as in claim 1, wherein X2 is Aib;
X3 is absent;
X33 is Leu;
U is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-};
W is -C(0)-NH-(CH2)4-NH-] and
Z is -C(0)-(CH2)n-C00H wherein n is integer 16.
5. The polypeptide as in claim 1, wherein X2 is Aib;
X3 is absent;
X33 is Leu;
U is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-};
W is
Z is -C(0)-(CH2)n-C00H wherein n is integer 16.
6. The polypeptide as in claim 1, wherein X2 is Aib;
X3 is absent;
X33 is Leu;
U is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-};
W is -C(0)-NH-(CH2)3-NH-] and
Z is -C(0)-(CH2)n-C00H wherein n is integer 16.
7. The polypeptide as in claim 1, wherein X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe);
X3 is absent;
X33 is Leu;
U is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-};
W is -C(0)-CH2-0-(CH2)2-0-(CH2)2-NH-], -C(0)-NH-(CH2)3-4-NH-], -C(0)- C(CH3)2-NH-] and
Z is -C(0)-(CH2)n-C00H or -C(0)-(CH2)n-CH3 wherein n is an integer from 14 to 20
8. The polypeptide as in claim 1, wherein W is selected from a group consisting of - C(0)-NH-(CH2)3-4-NH-], -C(0)-C(CH3)2-NH-] and
9. The polypeptide as in claim 1, wherein X2 is Ala;
X3 is absent;
X33 is Leu;
W is absent;
Z is -C(0)-(CH2)n-CH3 wherein n is integer 14.
10. The polypeptide as in claim 1, wherein X2 is Aib;
X3 is absent;
X33 is Leu;
W is absent;
Z is -C(0)-(CH2)n-CH3 wherein n is integer 14.