Long acting GLP-1 / GIP dual agonists

Abstract

The present invention relates to long acting glucagon-like peptide-1 and human glucose-dependent insulinotropic polypeptide (GIP) agonist polypeptides which may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity, obesity and hyperlipidemia.

Description

LONG ACTING GLP-1 / GIP DUAL AGONISTS FIELD OF THE INVENTION The present invention relates to a long acting glucagon-like peptide-1 and human glucose-dependent insulinotropic polypeptide / Gastro Intestinal Peptide (GIP) agonist polypeptide which may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity, obesity and hyperlipidemia. BACKGROUND OF THE INVENTION Treatment of type 2 diabetes mellitus (T2DM) with glucagon-like peptide-1 receptor agonists (GLP-1RAs) leads to improved glycaemic control, reduced body weight, and improvement in several cardiovascular risk factors. These benefits are mediated by the glucagon-like peptide-1 receptor (GLP-1R), a member of the class B family of G protein- coupled receptors, that is expressed in pancreatic beta-cells, various cell types of the gastrointestinal tract, and neurons throughout both the central (CNS) and the peripheral nervous systems. Activation of GLP-1R signaling by GLP-1RAs improves glucose homeostasis by enhancing glucose-stimulated insulin secretion, delaying gastric emptying, and decreasing plasma glucagon levels, and reduces body weight by activating anorexigenic pathways in the brain. Due to the glucose-dependence of beta-cell activation, GLP-1RAs are not associated with increased risk of hypoglycaemia. While the broad metabolic benefits of GLP-1RAs have established this class in the T2DM treatment paradigm, many patients do not reach their HbA lc / glycemic targets, and weight loss achieved with these agents thus requiring a higher dose, which also increases the GI adverse events, and remains well below what can be attained with bariatric surgery, the most potent clinical intervention for obesity. Thus, there are significant opportunities to improve upon the existing GLP-1RA class of therapeutics. One emerging approach is to combine foundational GLP-1RA therapy with pharmacological strategies targeting additional pathways implicated in nutrient and energy metabolism, such as glucose-dependent insulinotropic polypeptide (GIP). GIP is an incretin that is secreted from K cells in the upper small intestine, duodenum, in response to food. Postprandial GIP levels are approximately 4-fold higher compared to GLP-1 under normal physiological conditions. GIP is responsible for the majority of the insulinotropic incretin effect in man, and has important additional functions that are distinct from GLP-1. Unlike GLP-1, GIP is both glucagonotropic and insulinotropic in a glycemic-dependent manner, dose-dependently stimulating glucagon secretion under hypoglycemic conditions and insulin under hyperglycemic conditions, glucagon released does facilitate insulin secretion. Although both GIP-receptor (GIPR) and GLP-1R are present in beta-cells, GIPR expression is distributed differently in extra-pancreatic tissues as GIPR is abundant in adipose tissue and is found in many non-overlapping areas of the CNS. GIP is implicated in adipose tissue carbohydrate and lipid metabolism by its actions to regulate glucose uptake, lipolysis, and lipoprotein lipase activity. These findings suggest that pharmacological activation of GIPR may have a therapeutic benefit on peripheral energy metabolism. Recently, uni-molecular, multi-functional peptides that combine GLP-1RA activity with GIP activity have been suggested as new therapeutic agents for glycemic and weight control. United States Patent No. 9474780 discloses dual GLP-1 and GIP receptor agonists including tirzepatide. H © Ho a Ne LR BJA FV-Q WL 1AG-GP-5-5.G-APP-P-S-NH, H ok mona, emery EN “ Arn Tirzepatide Tirzepatide is under Phase-III clinical studies for T2DM and obesity. WIPO publication numbers WO201774714A1, ‘W0202023386A1, ‘W02020023388A1, WO2015067715A2, WO2016111971A1 and WO2013164483A1 disclose GLP-1 R and GIP R dual agonist compounds. SUMMARY OF THE INVENTION The present invention provides a polypeptide or pharmaceutically acceptable salt thereof, comprising an amino acid sequence: Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-Xaal5-K-I-A-Xaa19-X3-Xaa21-F-V-Xaa24-W-L-X4- A-G-G-P-S-S-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 1) wherein X1 is Aib, Ser(OMe) or (D)Ser(OMe); X2 is Tyr, Ser(OMe), (D)Ser(OMe) or Aib; X3 is Gln or Lys; wherein, when X3 is Lys, the side chain amino (€ amino) group of Lys is acylated with a moiety: —U=W=-Y=2Z wherein U is ~C(0)-CHz-0-(CH:)2-0O-(CH:)2-NH-} wherein } is the point of attachment with group W; W is selected from a group consisting of —C(0)-NH-(CHz),-NH-], -C(0)-C(CHz)2-NH-] and —C(0)-CH2-0-(CHz)2-0-(CHz)2-NH-], wherein p is 3 or 4 and wherein ] is the point of attachment with group Y; Y is-C(0)-(CH2):-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is —C(0)-(CH2)x-COOH or —-C(0)-(CH2)n-CH3 wherein n is an integer from 14 to 20; and with a proviso that when X3 is Lys and X2 is Aib, then W is not —-C(0)-CHz-0-(CHa)2- 0-(CHz)2-NH-]; X4 is Leu, Ile or Glu; X5 is absent, Arg or Lys; wherein, when X5 is Lys, the side chain amino (€ amino) group of Lys is acylated with a moiety: gE wherein U’ is —C(0)-CHz-0-(CHz)2-0-(CHz)2-NH-} wherein } is the point of attachment with group W’; ‘Wis selected from a group consisting of —~C(0)-NH-(CH2)¢-NH-], -C(0)-C(CH3)2-NH-] and —C(0)-CHz-0-(CH2)2-0-(CH2)2-NH-], q is 3 or 4 and wherein ] is the point of attachment with group Y’; Y’ is-C(0)-(CH2)2-CH(COOH)NH-- and -- is the point of attachment with the group Z’; Z’ is -C(0)-(CH2)m-COOH or —C(0)-(CH2)m-CH3 wherein m is an integer from 14 to 20; X6 is absent or Lys; X7 is absent or Lys; X8 is absent or Lys; X09 is absent or Lys; X10 is absent or Lys; X11 is absent or Lys; Xaal$5 is Asp or Glu; Xaal9 is Gln or Ala; Xaa2l is Ala or Glu; Xaa24 is Gln or Asn. wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as C-terminal primary amide; and with a proviso that at least one of X3 and X5 is Lys. ABBREVIATIONS Aib: 2-Aminoisobutyric acid DIPEA: N,N’ -Di-isopropylethyvlamine HOB: 1-Hydroxybenztriazole DIPC: N,N -Di-isopropvlcarbodiimide THF: Tetrahydrofuran DCM: Dichloromethane DMAP: 4-Dimethylaminopyridine DIC: Diisopropylcarbodiimide DMACc: Dimethylacetamide DETAILED DESCRIPTION OF THE INVENTION The present invention provides a stable long acting GLP-1 / GIP agonist polypeptide which may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity, obesity and hyperlipidemia. The polypeptides of present invention are believed to be long acting, which may not require frequent administration to a patient in need thereof. Accordingly, in one aspect the present invention provides a polypeptide or pharmaceutically acceptable salt thereof, comprising an amino acid sequence: Y-X1-E-G-T-F-T-S-D-Y-S-[-X2-L-Xaal5-K-I-A-Xaa19-X3-Xaa2 1-F-V-Xaa24-W-L-X4- A-G-G-P-§-S-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 1) wherein X1 is Aib, Ser(OMe) or (D)Ser(OMe); X2 is Tyr, Ser(OMe), (D)Ser(OMe) or Aib; X3 is Gln or Lys; wherein, when X3 is Lys, the side chain amino (€ amino) group of Lys is acylated with a moiety: U-W-Y—-2Z wherein U is ~C(0)-CHz-O-(CHz)2-O-(CH:2).-NH-} wherein } is the point of attachment with group W; W is selected from a group consisting of —C(0)-NH-(CH:),-NH-], —~C(0)-C(CHs)2-NH-] and —C(0)-CHz-0-(CHz)2-0-(CHz)2-NH-], wherein p is 3 or 4 and wherein ] is the point of attachment with group Y: Y is—C(0)-(CH2).-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is —C(0)-(CH2)»-COOH or —-C(0)-(CHa)s-CHs wherein n is an integer from 14 to 20; and with a proviso that when X3 is Lys and X2 is Aib, then W is not -C(0)-CHz-0-(CHa)2- 0-(CHz2)2-NH-]; X4 is Leu, Ile or Glu; X35 is absent, Arg or Lys; wherein, when X5 is Lys, the side chain amino (€ amino) group of Lys is acylated with a moiety: =u-w-y'-z' wherein U’ is —C(0)-CH2-0-(CHa)2-0-(CHz)2-NH-} wherein } is the point of attachment with group W’; W’ is selected from a group consisting of —C(0)-NH-(CHz2)¢-NH-], -C(0)-C(CH3)2-NH-] and —C(0)-CHz-0-(CHz)2-0-(CHa)2-NH-], wherein q is 3 or 4 and wherein ] is the point of attachment with group Y’; Y’ is-C(0)-(CH2)2-CH(COOH)NH-- and -- is the point of attachment with the group Z’; Z’ is -C(0)~(CH2)n-COOH or —C(0)~(CH2)m-CH3 wherein m is an integer from 14 to 20; X6 is absent or Lys; X7 is absent or Lys; X8 is absent or Lys; X9 is absent or Lys; X10 is absent or Lys; X11 is absent or Lys; Xaal$5 is Asp or Glu; Xaal9 is Gln or Ala; Xaa2l is Ala or Glu; Xaa24 is Gln or Asn; wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as C-terminal primary amide; and with a proviso that at least one of X3 and X5 is Lys. In one embodiment of the present invention, X1 is Aib. In another embodiment of the present invention, X2 is Aib. In another embodiment of the present invention, X1 and X2 both are Aib. In another embodiment of the present invention, X1 is Aib and X2 is Ser(OMe) or (D)Ser(OMe). In another embodiment of the present invention, X1 is Ser(OMe) or (D)Ser(OMe) and X2 is Aib. In another embodiment of the present invention, X4 is Leu or Ile. In another embodiment of the present invention, X4 is Ile. In another embodiment of the present invention, X5 is Lys or Arg. In another embodiment of the present invention, X3 is Lys and X35 is absent or Arg. In another embodiment of the present invention, X3 is Gln and X35 is Lys. In another embodiment of present invention, W is —C(0)-C(CH3)2-NH-]. In another embodiment of the present invention, W is —~C(O)-NH-(CHa)p-NH-], wherein pis 3 or 4. In another embodiment of the present invention, W is —C(0)-NH-(CH:)s-NH-]. In another embodiment of the present invention, W is —C(0)-CHz-0-(CHz)2-O- (CH1)2-NH-]. In another embodiment of present invention, W’ is —=C(0)-C(CH3)2-NH-]. In another embodiment of the present invention, W is —C(0)-NH-(CH2)q-NH-], wherein q is 3 or 4. In another embodiment of the present invention, W’ is —C(0)-NH-(CH2)s-NH-]. In another embodiment of the present invention, W’ is —C(0)-CH2-0-(CH:z)2-O- (CH1)2-NH-]. In another embodiment of the present invention, the C terminal amino acid is amidated as a C-terminal primary amide. In another embodiment of the present invention, the acid group of the C terminal amino acid is a free carboxylic acid. In another embodiment of the present invention, n is 16, 17, 18, 19 or 20. In a preferred embodiment n is 18 or 20. In yet another preferred embodiment n is 20. In another preferred embodiment, n is 16 or 18. In vet preferred embodiment, n is 18. In another embodiment of the present invention, Z is ~C(0)-(CH2)»-COOH and n is 16 or 18. In another embodiment of the present invention, m is 16, 17, 18, 19 or 20. In a preferred embodiment m is 18 or 20. In vet another preferred embodiment m is 20. In another preferred embodiment, m is 16 or 18. In vet preferred embodiment, m is 18. In another embodiment of the present invention, Z” is —C(0)-(CH2)m-COOH and m is 16 or 18. In another embodiment of the present invention, W is —~C(0)-NH-(CH:)+-NH-], Z is —C(0)-(CH2)»-COOH and n is 18. In another embodiment of the present invention, W is -C(0)-C(CHz)2-NH-], Z is — C(0)-(CH2)a-COOH and n is 16. In another embodiment of the present invention, W is -C(0)-C(CHz)2-NH-], Z is — C(0)-(CH2)n-COOH and n is 18. In another embodiment of the present invention, W is —~C(0)-CH2-0-(CH2):-O- (CH2)2-NH-], Z is -C(0)-(CH2)o-COOH and n is 16. In another embodiment of the present invention, W is —C(0)-CHz-0-(CHz)2-O- (CH2)2-NH-], Z is -C(0)-(CH2)s-COOH and n is 18. In another embodiment of the present invention, W* is —C(0)-NH-(CH2)+-NH-], Z’ is —~C(0)-(CH2)m-COOH and m is 18. In another embodiment of the present invention, W is —C(0)-C(CHs)2-NH-], Z” is —C(0)-(CH2)m-COOH and m is 16. In another embodiment of the present invention, W* is —C(0)-C(CHs)2-NH-], Z’ is —C(0)-(CH2)m-COOH and m is 18. In another embodiment of the present invention, W is ~C(0)-CHz-0-(CHz)2-O- (CH1)2-NH-], Z’ is -C(0)~(CH2)m-COOH and m is 16. In another embodiment of the present invention, W” is —C(0)-CH2-0-(CHz)2-O- (CH2)2-NH-], Z’ is -C(0)-(CH2)m-COOH and m is 18. In another embodiment of the present invention, X5, X6, X7, X8, X9, X10 and X11 are all absent. In another embodiment of the present invention, Xaal5 is Asp. In another embodiment of the present invention, Xaal9 is Gln. In another embodiment of the present invention, Xaa2l is Ala. In another embodiment of the present invention, Xaa24 is Gln. In another embodiment of the present invention, X1 is Aib and X2 is Ser(OMe) or Tyr. In another embodiment of the present invention, X1 is Aib and X2 is Ser(OMe). In another embodiment of the present invention, X1 is Aib and X2 is Tyr. In another embodiment of the present invention, X3 is Gln, In another embodiment of the present invention, X4 is Leu. In another embodiment of the present invention, X5 is Lys, wherein the side chain amino (€ amino) group of Lys is acylated with a moiety: u-w-y'=-2' In another embodiment of the present invention, W* is -C(0)-C(CHs)2-NH-], Z’ is —C(O)(CH2)m-COOH and m is 18. In another embodiment of the present invention, Xaal5 is Glu. In another embodiment of the present invention, Xaal9 is Ala. In another embodiment of the present invention, Xaa21 is Glu. In another embodiment of the present invention, Xaa24 is Asn. In another embodiment of the present invention, X6, X7, X8, X9, X10 and X11 are all absent. In another aspect, the present invention provides a polypeptide or pharmaceutically acceptable salt thereof, comprising an amino acid sequence: Y-Aib-E-G-T-F-T-$-D-Y-8-I-Ser(OMe)-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-X4-A-G-G-P- S-S-G-A-P-P-P-$-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 2), wherein X3 is Lys, wherein the side chain amino (€ amino) group of Lys is acylated with a moiety: LC U=W=Y=2Z wherein U is ~C(0)-CHz-0-(CH:)2-0O-(CH2)2-NH-} wherein } is the point of attachment with group W; W is selected from a group consisting of —C(0)-NH-(CHz),-NH-], -C(0)-C(CH3)2-NH-] and —C(0)-CHz-0-(CHa)2-0-(CHa)2-NH-], wherein p is 3 or 4 and wherein ] is the point of attachment with group Y: Y is—C(0)-(CH2)2-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is —C(0)-(CH2)s-COOH or —-C(0)-(CH2)n-CH3 wherein n is an integer from 14 to 20; X4 is Ile or Glu; X5 is absent or Arg; X6 is absent or Lys; X7 is absent or Lys; X8 is absent or Lys; X09 is absent or Lys; X10 is absent or Lys; X11 is absent or Lys; and wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide. In one embodiment of the present invention, X4 is Ile. In another embodiment of present invention, W is —C(Q)-C(CHz)2-NH-]. In another embodiment of the present invention, W is —C(O)-NH-(CH2),-NH-], wherein pis 3 or 4. In another embodiment of the present invention, W is —C(0)-NH-(CH:2)s-NH-]. In another embodiment of the present invention, W is —~C(0)-CH2-0-(CH2)2-O- (CH2)2-NH-]. In another embodiment of the present invention, the C terminal amino acid is amidated as a C-terminal primary amide. In another embodiment of the present invention, n is 16, 17, 18, 19 or 20. In a preferred embodiment n is 18 or 20. In vet another preferred embodiment n is 20. In another preferred embodiment, n is 16 or 18. In vet preferred embodiment, n is 18. In another embodiment of the present invention, Z is -C(0)-(CH2)o-COOH and n is 16 or 18. In another embodiment of the present invention, W is -C(0)-C(CH3)2-NH-], Z is — C(0)-(CH2)n-COOH and n is 16. In another embodiment of the present invention, W is ~C(0)-C(CHs)2-NH-], Z is — C(0)-(CH2)n-COOH and n is 18. In another embodiment of the present invention, W is —~C(0)-CH2-0-(CH2)2-O- (CH2)2-NH-], Z is -C(0)-(CH2)a-COOH and n is 16. In another embodiment of the present invention, W is —C(0)-CHz-0-(CH2)2-O- (CH2)2-NH-], Z is -C(0)-(CH2)a-COOH and n is 18. In another embodiment of the present invention, X35, X6, X7, X8, X9, X10 and X11 are all absent. In another aspect, the present invention provides a polypeptide or pharmaceutically acceptable salt thereof, comprising an amino acid sequence: Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-X4-A-G-G-P-S-S-G- A-P-P-P-S (Seq. ID 3) wherein X1 is Aib; X2 is Ser(OMe) or Aib; X4 is Ile or Glu; X3 is Lys wherein the side chain amino (€ amino) group of Lys is acylated with a moiety: U-W—Y—2Z wherein U is ~C(0)-CHz-0-(CH:)2-0O-(CH:):-NH-} wherein } is the point of attachment with group W; W is selected from a group consisting of —C(0)-NH-(CHz2),-NH-], -C(0)-C(CHs)2-NH-] and —C(0)-CH2-O-(CHz)2-O-(CH2):-NH-], wherein p is 3 or 4 and wherein ] is point of attachment with group Y: Y is—C(0)-(CH2)2-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is —C(0)-(CH2)s-COOH or —-C(0)-(CH2)n-CH3 wherein n is an integer from 14 to 20; and wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide; with a proviso that when X2 is Aib, then W is not —C(Q)-CH2-0-(CH:)2-0-(CH2)2-NH-]. In one embodiment of the present invention, X2 is Aib and X4 is Ile. In another embodiment of present invention, W is —C(0Q)-C(CH3)2-NH-]. In another embodiment of the present invention, W is—C(0)-NH-(CHz)p-NH-] and wherein pis 3 or 4. In another embodiment of the present invention, W is—C(Q)-NH-(CHz)s-NH-]. In another embodiment of the present invention, W is —~C(0)-CH2-0-(CH2)2-O- (CH2)2-NH-]. In another embodiment of the present invention, the C terminal amino acid is amidated as C-terminal primary amide. In another embodiment of the present invention, n is 16, 17, 18, 19 or 20. In a preferred embodiment n is 18 or 20. In yet another preferred embodiment n is 20. In another preferred embodiment, n is 16 or 18. In vet preferred embodiment, n is 18. In another embodiment of the present invention, Z is ~C(0)-(CH2)»-COOH and n is 16 or 18. In another embodiment of the present invention, W is ~C(0)-NH-(CHz2)+-NH-], Z is —C(0)-(CH2):-COOH and n is 18. In another embodiment of the, W is —C(0)-C(CH3)-NH-], Z is —C(O)~(CHz)n- COOHand nis 16. In another embodiment of the present invention, W is -C(0)-C(CHs)2-NH-], Z is — C(0)-(CH2)a-COOH and n is 18, In another embodiment of the present invention, X2 is Ser(OMe) and X4 is Ile. In another embodiment of the present invention, W is -C(0)-C(CHs)2-NH-], Z is — C(0)~(CH2)»-COOH and n is 16. In another embodiment of the present invention, W is —~C(0)-CH2-0-(CH2)2-O- (CH2)2-NH-], Z is -C(0)-(CH2)o-COOH and n is 16. In another embodiment of the present invention, W is —~C(0)-CH2-0-(CH2)2-O- (CH2)2-NH-], Z is -C(0)-(CH2)s-COOH and n is 18. In another aspect, the present invention provides a polypeptide or pharmaceutically acceptable salt thereof, comprising an amino acid sequence: Y-Aib-E-G-T-F-T-S-D-Y-8-I-Aib-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-Ile-A-G-G-P-S-S-G- A-P-P-P-S (Seq. ID 4) wherein X3 is Lys wherein the side chain amino (€ amino) group of Lys is acylated with a moiety: —_—y—-W=Y—-2 wherein U is ~C(0)-CH2-O-(CH2)2-0O-(CH2)2-NH-} wherein } is the point of attachment with group W; W is selected from a group consisting of ~C(0)-NH-(CHa)p-NH-] or —-C(0)-C(CH3)2-NH-], wherein p is 3 or 4 and wherein ] is the point of attachment with group Y; Y is—C(0)-(CH2).-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is —C(0)-(CH2)x-COOH or —~C(0)-(CHa)x-CH: wherein n is an integer from 14 to 20; and wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide. In another embodiment of present invention, W is —C(Q)-C(CH3)2-NH-]. In another embodiment of the present invention, W is—C(0)-NH-(CHa)p-NH-] and wherein pis 3 or 4. In another embodiment of the present invention, W is—C(Q)-NH-(CH:)s-NH-]. In another embodiment of the present invention, the C terminal amino acid is amidated as a C-terminal primary amide. In another embodiment of the present invention, n is 16, 17, 18, 19 or 20. In a preferred embodiment n is 18 or 20. In yet another preferred embodiment n is 20. In another preferred embodiment, n is 16 or 18, In vet preferred embodiment, n is 18. In another embodiment of the present invention, Z is -C(0)-(CH2)o-COOH and n is 16 or 18. In another embodiment of the present invention, W is —-C(0)-NH-(CHz)s-NH-], Z is —C(0)-(CH2)s-COOH and n is 18. In another embodiment of the present invention, W is -C(0)-C(CHz)2-NH-], Z is — C(0)-(CH2)n-COOH and n is 16. In another embodiment of the present invention, W is -C(0)-C(CHz)2-NH-], Z is — C(0)-(CH2)n-COOH and n is 18. In another aspect, the present invention provides a polypeptide or pharmaceutically acceptable salt thereof, comprising an amino acid sequences selected from: i) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gin Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser; ii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile D-Ser-(OMe) Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser; iii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser; iv) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Arg; v) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys Ile Ala Ala Tyr Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser X35; vi) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser X35; vii) Tyr D-Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser; and viii) Tyr Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln X3 Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser. wherein, X3 and X35 have the same meaning as set forth above; and wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide. In another aspect, the present invention provides a polypeptide or pharmaceutically acceptable salt thereof comprising an amino acid sequence selected from the group consisting of’ 1) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH: (SEQ ID NO 5); ii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile D-Ser-(OMe) Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (SEQ ID NO 9); iii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (SEQ ID NO 10); iv) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Arg (SEQ ID NO 11); v) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys-NH: (SEQ ID NO 12): vi) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys- NH: (SEQ ID NO 13): vii) Tyr D-Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH: (SEQ ID NO 6); and viii) Tyr Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NHz (SEQID NO 7). In another aspect, the present invention provides a polypeptide or pharmaceutically acceptable salt thereof, selected from the representative compounds as disclosed in the Table 1. In the embodiments of the present invention, the groups U, W, Y and Z in the moiety —y—-W=-yY—-2 or the groups U’, W’, Y’ and Z’ in the moiety —_—-W-Y'-Z have meaning as defined in this specification and should not be interpretted as or mixed with the single letter code of the amino acids; and wherein, the group -U-W-Y-Z and / or -U’-W’-Y’-Z" is selected from the representative structures of Moiety A, B, C, D and E as disclosed in Table 2. Ser(OMe) as described herein in the specification is amino acid serine, preferably the L isomer, with its hydroxyl group methylated and has following structure: Ne . . wy o ‘Wherever applicable, (D)Ser(OMe) refers to the D isomer of Ser(OMe). Tyr-(OEt) as described herein in the specification is amino acid tyrosine, preferably the L isomer, with the hydroxyl group ethylated and has the following structure (* denotes points of attachment to adjacent residues). Lr As iL» 3 LX 0 ‘Wherever applicable, (D)Tyr(OEt) refers to the D isomer of Tyr(OEt). The polypeptide sequences mentioned in the specification are represented either by the single letter code or three letter code of the amino acids as approved by IUPAC. Unless stated otherwise, the specification intends to cover both L and D isomers of the amino acids in the sequence. However, in preferred embodiments, all the amino acids are in “L” configuration unless indicated otherwise. A “Pharmaceutically acceptable salt” according to the invention includes an acid addition salt formed with either organic or inorganic acids. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which may be salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and the like or of organic acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, amino acids such as glutamic acid or aspartic acid, and the like. The pharmaceutically acceptable acid addition salts of the present invention include salts formed with the addition of one or more equivalents of acids, for example, monohydrochloride, dihydrochloride salts, etc. Salts can be prepared by any process under the purview of an ordinary person skilled in the art (see Berge et al, J. Pharm. Sci. 1977, 66, 1-19; and Handbook of Pharmaceutical Salts, Properties, and Use; Stahl and Wermuth, Ed.; Wiley-VCH and VHCA: Zurich, Switzerland, 2002). Table 1 provides some of the representative compounds of the present invention. Table 1: Representative polypeptide compounds of present disclosure Compd | Structure SEQ No. D gg — ——— — - 1 | vl _Fecrereoveil § Loko Larvawiacersscapprs, | C110 SEQ D Seq ID: 0s — EET - | ri Jearereoveil Livia Jarvaniircarsssrnoronm, J —. INC wo hs - 2 | oly dnnnrasnrend Luptied | JAF QL AGE PSS CARER EN, 1 ory 0 _ En To 3 | Y-(DjSer(OMe)EG-T-AT.SDY-5hR_ JL L-DKhAQ-], JL AF VQNLI40.0P SSC APPPSAN ) Moet, [ahi gg el TE | veppmnerensnnnil Lise J Ar vaniincorssaanpesiH, 3 ID: 1 woiaty Moiety 8B” on aI - 4 | verougeatersovef Lorine JAP QW LA Gop SS CAPR PEN, Seq ID: 1 Moity 5 5 oro rorrrsorei LL roeed Seq ID: WJ LJ fn Fra wba Gar sar prs, | SE 3 Moity 5 [5 TY = - 5 oon, Jeatrroovst Ep Seq ID: Y 08 wes HC H . 6 | i, Learrrsovs oseromsLoriaat Jarvaniiscesssoarprsm, Seq ID: 3 woiety 8 MH MoletyB —__ To J] 7 | vol JE GTR TS DS SoM LOK AGH JAF VQ WLIAG GPSS GAP PPENH, i ID: 1 Molety Pa Molety BZ H 2 Seq ID: 8 | wi Jearersorveit Lionel Larvawitacerssenreoony, x J Moisty EN MoE”. En To J] 9 | vol JE GTR Ts Ds SoMa DAG JAF WLIAG GPSS EAP PPENH, Fi ID: 1 Waety cH 7 Seq ID: 10 | wi Learersovsisaomioniaat JF VOW IA GP SSCAPP PENH, i 1 Molety 0H Molety O° 73 2 D: 1 v-R, eer rrsoysi—f_ I Lokraat JAF QUAIACOP SCAR PPSR Seq Y 11 1 Moisty BN MoietyB” 5 Seq ID: zo wh Jearrrsoveint, I Lowimal TL J yoy c” MoletyC~ 5 | ; 13 | wi Je errrsavsrsaonm oie] JAF vawLincepesaarppeNn, 39 ID: 1 Molety aN Molety A” grrr —T 14 | Yo JE GTR TS DY SAY LEK LAA QE FNAL AGEP-5-564P-0P-5- J Seq. YM: | ID: 12 oie o 15 vi Jeerrrenvarse & Seq. a G-TF-T-6.D-Y-6 + Ser(OMe)-L-E-K--A-A-Q-EF-VN-W-LLAG-G-P-s-8-c-AP-PPeN JL | 20 ha APPR Jo a SL iW H fE] | wi J eerrreoveramomierintassuniniiaserescip re J 1 Mole 5 16 Hg H Mm YN E-G-T-F-T-8-D-Y-8-—, LD-K-AQN oF -V / -Q-W-L-I-A-G-G-P-5-5-G-A-P-P-P-5-R 1 1 —_— — —_ Molety gM 16 SJ eorrrsovsit I Lowiaal I Seq ID: | - Ade -G-T-F-T-§-D-Y-8-I~, L-D-Kl-A-Q y oF -V-Q-W-L+I-A-G-G-P-5-5-G-A-P-P-P-§-R 1 1 Molety 0-M *Unless stated otherwise all the amino acids mentioned are in “L” configuration. wherein, the structures of Moieties A, B, C & D are disclosed in Table 2. Table 2: Structure of Moiety A, B,C,D and E Moiety A | a EN ee | HO oS OH o Molety A — Ne o | oS ° a Molety B © Moiety C ——— ot reels, gn I NN ox ~o HO. or [rong Se 0 OH or o Moiety C Moiety-D — optrenAAAno Oo | enw o PPP PNP NNN NL = 0 Maiety D Moiety E = CAN nA HO | Yr PANNA Moiety E © In another aspect, the present invention provides a method of treating or preventing hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers in a patient, comprising administering to a patient in need thereof, an effective amount of a polypeptide of the present invention or pharmaceutically acceptable salt thereof. In another aspect, invention provides a method of treatment of type 2 diabetes in a patient comprising administering to a patient in need of such treatment an effective amount of a polypeptide of the present invention or a pharmaceutically acceptable salt thereof. In another aspect, invention provides a method of treatment of obesity in a patient comprising administering to a patient in need of such treatment an effective amount of a polypeptide of the present invention or a pharmaceutically acceptable salt thereof. In another aspect, invention provides a method of treatment of hyperlipidemia in a patient comprising administering to a patient in need of such treatment an effective amount of a polypeptide of the present invention or a pharmaceutically acceptable salt thereof. The term “effective amount or amount effective” as used herein refers to an amount of the polypeptide which is sufficient, upon single or multiple dose administration(s) to a subject, in curing, alleviating, relieving or partially addressing the clinical manifestation of given disease or state and its complications beyond that expected in the absence of such treatment. Thus, the result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. It is understood that “a therapeutically effective amount” can vary from subject to subject depending on age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In another aspect, the present invention provides a pharmaceutical composition comprising a polypeptide of the present invention or pharmaceutically acceptable salt thereof with one or more of a pharmaceutically acceptable carrier, diluent, or excipient. The polypeptides of the present invention or pharmaceutically acceptable salts thereof are preferably formulated as pharmaceutical compositions administered by parenteral routes (e.g.. subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal). Such pharmaceutical compositions and processes for preparing same are well known in the art. (See, ¢.g., Remington: The Science and 50 Practice of Pharmacy (D. B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006). In another aspect, the present invention provides a polypeptide of the present invention or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising a polypeptide of the present invention or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease in a patient, wherein said disease is selected from the group consisting of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type . diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers. In some embodiments, the polypeptide or pharmaceutically acceptable salt thereof or a pharmaceutical composition is provided simultaneously, separately, or sequentially in combination with an effective amount of one or more additional therapeutic agents. The present invention may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments. Examples: Instruments and analytical methods: Instruments used for characterization and analysis of the compounds of the present invention are HPLC (Waters e2695 Alliance; Detector ‘Waters (2489 UV / Visible)). Mass instrument: HPLC: Waters ¢2695 Alliance; Detector: Acquity- QDa. The final compounds of the present disclosure were purified by preparative HPLC procedure as outlined below: Preparative HPLC: WATERS 2555 Quaternary gradient module (Max Total Flow: 300 mL / min, Max Pressure: 3000 psi) or Shimadzu LC-8A (Max Total Flow: 150 mL, Max Pressure: 30 Mpa), Column: Phenyl, 10u Flow: 75SmL / min Mobile Phase: For first purification For second purification For third purification Mobile PH 8.0 Phosphate buffer 1% Acetic acid in water pH 8.2 Ammonium formate Phase A buffer Mobile Acetonitrile 1% Acetic acid in | Acetonitrile Phase B Acetonitrile:n-Propanol 50:50 Gradient 15 to 45% Mobile Phase-B | 20 to 50 % Mobile Phase-B | 20 to 50% Mobile Phase-B in 300 min in 250 min in 250 min The purity of the compounds of the present disclosure was analyzed by RP-HPLC method as outlined below: HPLC Method B1: Column: YMC Pack-Phenyl (4.6 mm X 150 mm 3p) Eluent: Mobile Phase A: 0.1 % Trifluroacetic acid in Water Mobile phase B: 0.1 % Trifluroacetic acid in Acetonitrile Flow rate: 1.5 mL / min Detection: UV detection at 210 nm Column Temperature: 50 °C Run Time: 50 min. Gradient: Time Mobile Phase A % Mobile Phase B % 0.01 90 10 35.0 20 RO 40.0 20 80 41.0 90 10 50.0 90 10 HPLC Method B2: Column: Xbridge Peptide BEH C18 (4.6 mm x 250 mm, 3.51) Eluent: Mobile Phase A: Buffer: Acetonitrile (900: 100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer: Potassium dihydrogen orthophosphate in water, pH adjusted to 3.0£0.1 with orthophosphoric acid Flow rate: 1.0 mL / min Detection: UV detection at 210 nm Column Temperature: 65 °C Sample Tray temperature: 5 °C Run Time: 40 min. Time ‘Mobile Phase A % ‘Mobile Phase B % 0 55 45 5 41 59 35 40 60 351 55 45 40 55 45 Method B3: Column: Xbridge Peptide BEH C18 (4.6 mm x 250 mm, 3.51) Eluent: Mobile Phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer: Potassium dihydrogen orthophosphate in water, pH adjusted to 3.0£0.1 orthophosphoric acid Flow rate: 1.0 mL / min Detection: UV detection at 210 nm Column Temperature: 65 °C Sample Tray temperature: 5 °C Run Time: 65 min. Time ‘Mobile Phase A % ‘Mobile Phase B % 0 55 45 5 40 60 60 35 65 60.1 55 45 65 35 45 Method B4: Column: Xbridge Peptide BEH C18 (4.6 mm x 250 mm, 3.51) Eluent: Mobile Phase A: Buffer; Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer: Potassium dihydrogen orthophosphate in water, pH adjusted to 3.0£0.1 orthophosphoric acid Flow rate: 0.8 mL / min Detection: UV detection at 210 nm Column Temperature: 65 °C Sample Tray temperature: 3 °C Run Time: 90 min. Time ‘Mobile Phase A % ‘Mobile Phase B % 0 55 45 3 55 45 5 40 60 60 30 61 65 0 100 75 0 100 7501 35 45 90 55 45 Method BS: Column; Xbridge Peptide BEH C18 (4.6 mm x 250 mm, 3.5) Eluent: Mobile Phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700) Buffer: Potassium dihydrogen orthophosphate in water, pH adjusted to 3.0£0.1 with orthophosphoric acid Flow rate: 1.0 mL / min Detection: UV detection at 210 nm Column Temperature: 65 °C Sample Tray temperature: 10 °C Run Time: 60 min. Time Mobile Phase A % Mobile Phase B % 0 35 45 3 41 59 50 40 60 51 55 45 60 55 45 Method of Preparation: Example 1. Preparation of 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo- octadecanoyl)amino]-5-oxo-pentanoyl] amino]-2-methyl-propanoyl] amino]ethoxy]ethoxy]acetic acid (Moiety A-di-fert-butyl ester) 0 o nd NO OH XC NH a 5 Nw > I PANNA > Arba tabi ih Shar 0 Molety A-dl-tert-buty| ester Moiety A- di-tert-butyl ester was prepared using solid phase synthesis using 2- chlorotrityl chloride resin. 2-[2-(2-Fmoc-aminoethoxy)ethoxyJacetic acid was attached to 2-chlorotrityl chloride resin in presence of DIPEA to yield 2-[2-(2-Fmoc- aminoethoxy)ethoxy]acetic acid-2-Cl-Trt-Resin. The Fmoc protecting group was removed by selective de-blocking of amino group using piperidine followed by coupling with Fmoc- Aib-OH in THF: DMAc / THF using DIPC and HOBt which yielded 2-[2-[2-[(2-Fmoc- amino-2-methyl-propanoyl)aminoJethoxy JethoxyJacetic acid-2-Cl-Trt-Resin. The Fmoc group was removed by selective de-blocking using piperidine and the free amino group was coupled with Fmoc-Glu-OtBu using HOBt and DIPC to vield 2-[2-[2-[[2-[[(45)-4-Fmoc- amino-5-tert-butoxy-5-oxo-pentanoyl]amino]-2-methyl-propanoyl] amino] ethoxy]Jethoxy]acetic acid-2-Cl-Trt-Resin. The Fmoc group of the resultant compound was selectively de-blocked using piperidine and the free amino group was then coupled with octadecanedioic acid mono fert butyl ester to give 2-[2-[2-[[2-[[(45)-5-tert-butoxy-4-[(18- tert-butoxy-18-oxo0-octadecanoyl)amino]-5-oxo-pentanoyl]amino]-2-methyl-propanoyl]- amino]ethoxy]ethoxylacetic acid-2-CI-Trt-Resin. The intermediate was then cleaved from 2-Cl-Trt-Resin using trifluoroethanol: DCM (1:1) to obtain the title compound (Moiety A- di-tert-butyl ester). (LCMS= m / z: 786.39 (M+H")). Example 2. Preparation of 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4- [(20-tert-butoxy-20-oxo- icosanoyl)amino]-5-0xo-pentanoyl]amino]-2-methyl-propanoyl] amino]ethoxy]ethoxy]acetic acid (Moiety B-di-fert-butyl ester) o nl AON OH ~~ NH Y Molety B-dl-fert-butyl ester 2-[2-[2-[[2-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentanoylJamino]-2-methyl- propanoyl] amino] ethoxy]ethoxy]acetic acid-2-Cl-Trt-Resin was prepared as described in Example | and was subjected to selective de-protection using piperidine and the free amino group was then coupled with 20-(tert-butoxy)-20-oxoicosanoic acid to give 2-[2-[2-[[2- [[(4S)-5-tert-butoxy-4-[(20-tert-butoxy-20-ox0-icosanoyl)amino] -5-oxo- pentanoyl]amino]-2-methyl-propanoyl]amino] ethoxylethoxylacetic acid-2-Cl-Trt-Resin. The intermediate was then cleaved from 2-Cl-Trt-Resin using trifluoroethanol:DCM (1:1) to obtain the tile compound (Moiety B-di-fers-butyl ester). (LCMS= m / z: 814.10 (M+H")). Example 3: Preparation of 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(18-tert-butoxy-18-ox0- octadecanoyl)amino]-5-o0xo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid (Moiety C-di- tert-butyl ester) Q osm yO 2H Bi Or Y PANN ~ Qo Moiety C-di-fert-butyl ester Moiety C-di-ferr-butyl ester was prepared using solid phase synthesis using 2- chlorotrityl chloride resin. 2-[2-(2-Fmoc-aminoethoxy)ethoxyJacetic acid was attached to 2-chlorotrityl chloride resin in presence of DIPEA to yield 2-[2-(2-Fmoc- aminoethoxy)ethoxy]acetic acid-2-Cl-Trt-Resin. The Fmoc protecting group was removed by selective de-blocking of amino group using piperidine followed by coupling with 2-[2- (2-Fmoc-aminoethoxy)ethoxy]acetic acid in THF using DIPC and HOBt which yielded {(Fmoc-amino-ethoxy)-ethoxy } -acetyl-{(-amino-ethoxy)-ethoxy}-acetic acid-2-Cl-Trt- Resin The Fmoc group was removed by selective de-blocking using piperidine and the free amino group was coupled with Fmoc-Glu-OtBu using HOBt and DIPC to yield Fmoc- Glu({(amino-ethoxy)-ethoxy } -acetyl-{(-amino-ethoxy)-ethoxy } -acetic acid-2-Cl-Trt- Resin )-OtBu The Fmoc group of the resultant compound was selectively de-blocked using piperidine and the free amino group was then coupled with octadecanedioic acid mono tert butyl ester to give 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[( 18-tert-butoxy-18-0x0- octadecanoyl)amino]-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetylJamino]ethoxy]ethoxylacetic acid-2-Cl-Trt-Resin. The intermediate was then cleaved from 2-Cl-Trt-Resin using trifluoroethanol:DCM (1:1) to obtain 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(18-tert-butoxy-18-0x0- octadecanoyl)amino]-5-oxo- pentanoyl]Jamino]ethoxy]ethoxy]acetylJamino]ethoxylethoxylacetic acid (Moiety C-di- tert-butyl ester) (LCMS= m / z: 846.10 (M+H")). Example 4: Preparation of 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(20-tert-butoxy-20-oxo- icosanoyl)amino]-5-oxo- pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid. (Moiety D- di-tert-butyl ester) o apron mon o 2 «Sa ha SSS SY oy 0 Moiety D- di-fert-butyl ester Moiety D-di-tert-butyl ester was prepared using solid phase synthesis using 2- chlorotrityl chloride resin as schematically represented below. 2-[2-(2-Fmoc- aminoethoxy)ethoxyJacetic acid was attached to 2-chlorotrityl chloride resin in presence of DIPEA to yield 2-[2-(2-Fmoc-aminoethoxy)ethoxy]Jacetic acid-2-Cl-Trt-Resin. The Fmoc protecting group was removed by selective de-blocking of amino group using piperidine followed by coupling with 2-[2-(2-Fmoc-aminoethoxy)ethoxyJacetic acid in THF using DIPC and HOBt which yielded {(Fmoc-amino-ethoxy)-ethoxy}-acetyl-{(-amino-ethoxy)- ethoxy} -acetic acid-2-Cl-Trt-Resin The Fmoc group was removed by selective de-blocking using piperidine and the free amino group was coupled with Fmoc-Glu-OtBu using HOBt and DIPC to yield Fmoc-Glu({(amino-ethoxy)-ethoxy } -acetyl-{(-amino-ethoxy)-ethoxy} - acetic acid-2-Cl-Trt-Resin )-OtBu The Fmoc group of the resultant compound was selectively de-blocked using piperidine and the free amino group was then coupled with 20- (tert-Butoxy)-20-oxoicosanoic acid to give 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(20-tert-butoxy-20-0x0-icosanoyl)amino]-5- oxo-pentanoyl]amino]ethoxy]ethoxylacetyl]amino]ethoxy]ethoxy]acetic acid -2-Cl-Trt- Resin. The intermediate was then cleaved from 2-Cl-Trt-Resin using trifluoroethanol: DCM (1:1) to obtain 2-[2-[2-[[2-[2-[2-[[5-tert-butoxy-4-[(20-tert-butoxy-20-ox0-icosanoyl)amino]-5- oxo-pentanoyl]amino]ethoxy]ethoxylacetyl]amino]ethoxy]ethoxy]acetic acid (Moiety D- di-tert-butyl ester) (LCMS= m / z: 874.15 (M+H")). Example 5: Preparation of 2-[2-[2-[4-[[5-tert-butoxy-4-[(20-tert-butoxy-20-oxo- icosanoyl)amino]-5-oxo-pentanoyl]amino]butylcarbamoylamino]ethoxy]ethoxy] acetic acid (Moiety E-di-tert-butyl ester) Qo ao A 0 5 REN x 1 AANA Moiety E-di-fert-butyl ester Moiety E-di-tert-butyl ester was prepared using solid phase synthesis using 2- chlorotrityl chloride resin. 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid was attached to 2-chlorotrityl chloride resin in presence of N,N -di-isopropylethylamine (DIPEA) to yield 2-[2-(2-Fmoc-aminoethoxy)ethoxyJacetic acid-2-Cl-Trt-Resin. The Fmoc protecting group was removed by selective de-blocking of amino group using piperidine and the free amino group was then activated using p-nitrophenylchloroformate in THF and DIPEA followed by reaction with Fmoc-amino butylamine hydrochloride salt in THF: DMAc in presence of DIPEA which yielded 2-[2-[2-(4-Fmoc-aminobutylcarbamoylamino)ethoxyJethoxy]acetic acid-2-Cl-Trt-Resin. The Fmoc group was removed by selective de-blocking using piperidine and the free amino group was then coupled to Fmoc-Glu-OtBu using 1- hydroxybenztriazole (HOBt) and N,N'-di-isopropylcarbodiimide (DIPC) which yielded 2- [2-[2-[4-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-0x0- pentanoylJamino]butylcarbamoylamino]ethoxy Jethoxy Jacetic acid-2-Cl-Trt-Resin which was selectively deblocked using piperidine and then coupled with 20-(tert-Butoxy)-20- oxoicosanoic acid to give intermediate 2-[2-[2-[4-[[5-tert-butoxy-4-[(20-tert-butoxy-20- oxo-icosanoyl)amino]-5-oxo- pentanoyl]amino]butylcarbamoylamino]ethoxy JethoxyJacetic acid -2-Cl-Trt-Resin. The intermediate was then cleaved from 2-Cl-Trt-Resin using trifluoroethanol: DCM (1:1) to obtain 2-[2-[2-[4-[[5-tert-butoxy-4-[(20-tert-butoxy-20-oxo-icosanoyl)amino]-5-oxo- pentanoyl]amino]butylcarbamoylamino]ethoxy JethoxyJacetic acid (LCMS= m / z: 843.14 (M+H"). (Moiety E-di-tert-butyl ester). Example 6: Preparation of Compound 1 The parent peptide was synthesized by solid-phase method. The starting resin used for synthesis was Fmoc-Rink amide resin. Selectively de-blocking of Fmoc protected amino group of rink amide resin using piperidine followed by coupling of Fmoc-Ser(tBu)- OH with the Rink amide resin. The coupling was performed by using DIPC-HOBt to yield Fmoc-Ser(tBu)-Rink amide Resin, this complete one cycle. Acetic anhydride and DIPEA / pyridine was used to terminate / cap the uncoupled amino groups at every amino acid coupling. Selective de-blocking of amino group of Fmoc-Ser(tBu)-Rink amide Resin using piperidine, then coupling with Fmoc-Pro-OH using HOBt and DIPC yielded Fmoc-Pro- Ser(tBu)-rink amide Resin. This completes 2™ cycle. Acetic anhydride and DIPEA / pyridine was used to terminate the uncoupled amino groups at every amino acid coupling. The above 3 steps, i.¢., selective Capping, deblocking of Fmoc- protection of amino acid attached to the resin and coupling of next amino acid residue in sequence with Fmoc- protected amino group were repeated for remaining 36 amino acid residues and last coupling was done with Boc protected amino acids (ie, Boc-Tyr (tBu)-OH). The selective deblocking, i.e.., capping of uncoupled amino group done by using Acetic anhydride and DIPEA / pyridine, deprotection of Fmoc group was done using piperidine and coupling with next Fmoc and / or Bog protected amino acid was done using HOBt / DIPC. The side chain of the Fmoc / Boc -protected amino acids were protected orthogonally, e.g., hydroxyl group of Serine, Tyrosine or Threonine were protected with ferz-butyl(-tBu) group, amino group of Lysine was protected with ferr-butyloxycarbonyl (-Boc) and (4,4-dimethyl-2.6- dioxocyclohex-1-ylidene)-3-methylbutyl (IVDde) group respectively, carboxylic acid groups of aspartic acid or glutamic acid were protected with tBu group and amide group of glutamine was protected with trityl (-Trt) group. The above mentioned three steps, i.e., selective capping, deblocking and then coupling with next Fmoc protected amino acids were performed and also Boc-Tyr(tBu)-OH is used at last to get Boc-Tyr(tBu)-Aib- Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib— Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-GIn(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu- Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. De-protection of IVDde group of peptide resin using hydrazine hydrate followed by coupling of Moiety A-di-tert butyl ester was performed by using DIPC-HOB to yield protected Compound 1 resin. Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(NH- Moiety A di-tert-butyl ester)-Ala-Phe-Val-GIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Cleavage and de-protection using tri-fluoroacetic acid with ethane-1,2-dithiol and tri-isopropylsilane followed by purification through preparative HPLC resulted in Compound 1. The HPLC purity of Compound 1 was assessed by Method B2. Mass (LCMS): m / z = 1182.41 (MH: *°), Calculated Mass= 4725.61; HPLC Purity: 97.77 % (Method B2), RT=19.9 min, Example 7: Synthesis of Compound 2 Compound 2 was prepared by solid phase method as per the analogous process given for Example 6, except here Moiety B-di-tert butyl ester was coupled with Peptide resin, followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 2. The HPLC purity of Compound 2 was assessed by Method B2. Mass (LCMS): m / z = 1189.36 (MH: +), Calculated Mass= 4753.41; HPLC Purity: 94.50 9% (Method B2), RT=22.1 min. Example 8: Synthesis of Compound 3 The parent peptide was synthesized by solid-phase method. The starting resin used for synthesis was Fmoc-Rink amide resin. Selectively de-blocking of Fmoc protected amino group of rink amide resin using piperidine followed by coupling of Fmoc-Ser(tBu)- OH with the Rink amide resin. The coupling was performed by using DIPC-HOB to yield Fmoc-Ser(tBu)-Rink amide Resin, this complete one cycle. Acetic anhydride and diisopropylethyl amine / pyridine was used to terminate / cap the uncoupled amino groups at every amino acid coupling. Selective de-blocking of amino group of Fmoc-Ser(tBu)-Rink amide Resin using piperidine, then coupling with Fmoc-Pro-OH using HOBt and DIPC yielded Fmoc-Pro-Ser(tBu)-rink amide Resin. This completes 2™ cycle. Acetic anhydride and diisopropylethyl amine / pyridine was used to terminate the uncoupled amino groups at every amino acid coupling. The above 3 steps, i.¢., selective Capping, deblocking of Fmoc- protection of amino acid attached to the resin and coupling of next amino acid residue in sequence with Fmoc- protected amino group were repeated for remaining 37 amino acid residues. The selective deblocking, i.e. capping of uncoupled amino group done by using Acetic anhydride and diisopropylethylamine / pyridine, deprotection of Fmoc group was done using piperidine and coupling with next Fmoc protected amino acid was done using HOBt / DIPC. The side chain of the Fmoc-protected amino acids were protected orthogonally, e.g., hydroxyl group of serine was protected with tert-butyl(-tBu) group and O-Methyl (OMe) group, Tyrosine or Threonine were protected with rerr-butyl(tBu) group, amino group of Lysine was protected with ferr-butyloxycarbonyl (-Boc) and (4.4-dimethyl-2,6-dioxocyclohex-1- ylidene)-3-methylbutyl (IVDde) group respectively, carboxylic acid groups of aspartic acid or glutamic acid were protected with —tBu group and amide group of glutamine was protected with trityl (-Trt) group. The above mentioned three steps, i.e., selective capping, deblocking and then coupling with next Fmoc protected amino acid were performed to get Fmoc-Tyr(tBu)-(D)Ser(OMe)-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(IVDde)-Ala-Phe-Val-GIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. De-blocking of ~~ Fmoc-Tyr(tBu)-(D)Ser(OMe)-Glu(OtBu)-Gly-Thr(tBu)-Phe- Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile- Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. using piperidine followed by Boc protection of Peptide resin using Boc anhydride to yield Boc-Tyr(tBu)-(D)Ser(OMe)- Glu(otBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib— Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-GIn(Trt)-Lys(IVDde)- Ala-Phe-Val-Gln(Trt)-Trp-Leu- Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. De-protection of IVDde group of peptide resin using Hydrazine hydrate followed by coupling of moiety B-di-fert butyl ester was performed by using diisopropylcarbodiimide, N-hydroxybenzotriazole (DIPC-HOB) as coupling reagent in presence of which yielded Compound 3 resin. Boc-Tyr(tBu)-(D)Ser(OMe)-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-GlIn(Trt)- Lys(NH.- moiety B-di-tert butyl ester)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Cleavage and de- protection using trifluoroacetic acid with ethane-1,2-dithiol and triisopropylsilane followed by purification through preparative HPLC resulted in Compound 3. The HPLC purity of Compound 3 was assessed by Method B2. Mass (LCMS): m / z = 1193.70 (MH, +), Calculated Mass=4770.77; HPLC Purity: 91.96 9% (Method B2), RT=29.0 min. Example 9: Synthesis of Compound 4 Compound 4 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 4 Fmoc-Ser(OMe)-OH was used at position 2 instead of Fmoc-D-Ser(OMe)-OH to get Boc-Tyr(tBu)-Ser(OMe)-Glu(OtBu)-Gly-Thr(tBu)-Phe- Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile- Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety B- di-tert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 4. The HPLC purity of Compound 4 was assessed by Method B2. Mass (LCMS): m / z = 1193.68 (MH, **), Calculated Mass= 4770.69; HPLC Purity: 95.52 9% (Method B2), RT=26.2 min, Example 10: Synthesis of Compound 5 Compound 5 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 5 Fmoc-(D)-Tyr(OEt)-OH was used at position 1 instead of Fmoc-Tyr(tBu)-OH and Fmoc-Aib-OH was used at position 2™ instead of Fmoc- D-Ser(OMe)-OH to get Boc-(D)-Tyr(OEt)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety B-di-fert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 5. The HPLC purity of Compound 5 was assessed by Method B3. Mass (LCMS): m / z = 1196.34 (MH: *°), Calculated Mass= 4781.33; HPLC Purity: 93.86 9% (Method B3), RT=38.8 min. Example 11: Synthesis of Compound 6 Compound 6 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 6 Fmoc-(D)Ser (OMe)-OH was used at position 13 instead of Fmoc-Aib-OH and Fmoc-Aib-OH was used at position 2° instead of Fmoc-D- Ser(OMe)-OH to get Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-(D)Ser(OMe)-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-GIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety B-di-fert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 6. The HPLC purity of Compound 6 was assessed by Method B2. Mass (LCMS): m / z = 1191.03 (MHs +), Calculated Mass: 4768.15; HPLC Purity: 94.74% (Method B2), RT=27.1 min. Example 12: Synthesis of Compound 7 Compound 7 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 7 Fmoc-Ser(OMe)-OH was used at position 13 instead of Fmoc-Aib-OH and Fmoc-Aib-OH was used at position 2° instead of Fmoc-D- Ser(OMe)-OH to get Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(IVDde)-Ala-Phe-Val-Gin(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety B-di-fert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 7. The HPLC purity of Compound 7 was assessed by Method B2. Mass (LCMS): m / z= 1193.67(MH: *°), Calculated Mass= 4770.65; HPLC Purity: 95.4 9% (Method B2), RT=26.4 min. Example 13: Synthesis of Compound 8 Compound 8 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 8 Fmoc-Aib-OH was used at position 2 instead of Fmoc-D-Ser(OMe)-OH to get Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-GIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety E-di-tert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound purification using HPLC resulted in Compound 8. The HPLC purity of Compound 8 was assessed by Method B4. Mass (LCMS): m / z = 1196.55 (MHa +7), Calculated Mass=4782.168; HPLC Purity: 97.37 9% (Method B4), RT=25.6 min. Example 14: Synthesis of Compound 9 Compound 9 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 9 Fmoc-Ser(OMe)-OH was used at position 13 instead of Fmoc-Aib-OH and Fmoc-Aib-OH was used at position 2 instead of Fmoc-D- Ser(OMe)-OH to get Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)- Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)- Lys(IVDde)-Ala-Phe-Val-GlIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly- Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety C-di-fert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 9. The HPLC purity of Compound 9 was assessed by Method B2. Mass (LCMS): m / z = 1201.7 (MHz **), Calculated Mass= 4802.8; HPLC Purity: 97.30 % (Method B2), RT=15.3 min. Example 15: Synthesis of Compound 10 Compound 10 was prepared by solid phase method as per the analogous process given for Example 8, wherein for Compound 10 Fmoc-Ser (OMe)-OH was used at position 13 instead of Fmoc-Aib-OH and Fmoc-Aib-OH was used at position 2 instead of Fmoc- D-Ser(OMe)-OH to get Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-lle-Ser(OMe)-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-GIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Rink amide resin. Then coupling with Moiety D-di-fert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 10. The HPLC purity of Compound 10 was assessed by Method B2. Mass (LCMS): m / z = 1610.78 (MH; 7), Calculated Mass= 4829.316; HPLC Purity: 93.41 % (Method B2), RT=20.3 min. Example 16: Synthesis of Compound 11 The parent peptide was synthesized by solid-phase method. The starting resin used for synthesis was Wang resin. Fmoc protected Arg(pbf) was used for coupling with the Wang resin. The coupling was performed by using diisopropylcarbodiimide, N- hydroxybenzotriazole (DIC-HOBt) as coupling reagent in presence of 4- dimethylaminopyridine (DMAP) which yielded Fmoc-Arg(pbf)-Wang Resin. Selective de- blocking of amino group of Fmoc-Arg(pbf)-Wang Resin using piperidine followed by coupling with Fmoc-Ser(tBu)-OH using HOBt / DIPC yielded Fmoc-Ser(tBu)-Arg(pbf)- Wang Resin. This completes one cycle. Acetic anhydride and diisopropylethyl amine / pyridine was used to terminate the uncoupled amino groups at every amino acid coupling. The above 3 steps i.e., selective de-blocking of Fmoc- protection of amino acid attached to the resin, coupling of next amino acid residue in sequence with Fmoc-protected amino group and capping were repeated for remaining 38 amino acid residues, The side chain of the Fmoc-protected amino acids were protected orthogonally, e.g., hydroxyl group of Serine, Tyrosine or Threonine were protected with tert-butyl(-tBu) group, amino group of Lysine was protected with tert-butyloxycarbonyl (-Boc) and (4,4-dimethyl-2,6- dioxocyclohex-1-ylidene)-3-methylbutyl (IVDde) group respectively and carboxylic acid groups of aspartic acid or glutamic acid were protected with —tBu group, amide group of glutamine was protected with trityl (-Trt) group and Side chain of arginine protected with pbf group. The above mentioned three steps, i.e., selective capping, deblocking and then coupling with next Fmoc protected amino acid were performed to get Fmoc-Tyr(tBu)-Aib- Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib— Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu- Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(pbf)-Wang resin. De-blocking of Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala- Gln(Trt)-Lys(IVDde)-Ala-Phe-Val-GIn(Trt)-Trp-Leu-Ile-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(pbf)-Wang resin , using piperidine followed by Boc protection of Peptide resin using Boc anhydride to yield Boc-Tyr(tBu)-Aib- Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Aib— Leu-Asp(OtBu)-Lys(Boc)-Ile-Ala-GlIn(Trt)-Lys(IVDde)-Ala-Phe-Val-Gln(Trt)-Trp-Leu- Ile-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Arg(pbf)-Wang resin. De-protection of IVDde group of peptide resin was done using hydrazine hydrate and then it was coupled with Moiety B-di-fert butyl ester using diisopropylcarbodiimide, N- hydroxybenzotriazole (DIPC-HOBt) as coupling reagent to yield intermediate protected Compound 11 resin. Cleavage and de-protection from resin using trifluoroacetic acid with ethane-1,2-dithiol, triisopropylsilane followed by purification through preparative HPLC resulted in Compound 11. The HPLC purity of Compound 11 was assessed by Method B2. Mass (LCMS): m / z = 1228.8 (MH +), Calculated Mass= 4911.17, HPLC Purity: 98.22 9% (Method B2), RT=23.3 min. Example 17: Synthesis of Compound 12 Compound 12 was prepared by solid phase method as per the analogous process given for Example 16 except here Moiety C-di-tert butyl ester was coupled with Peptide resin, followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 12. The HPLC purity of Compound 12 was assessed by Method B2. Mass (LCMS): m / z = 1236.56 (MH; **), Calculated Mass= 4942.21; HPLC Purity: 97.2 % (Method B2), RT=11.703min. Example 18: Synthesis of Compound 13 Compound 13 was prepared by solid phase method as per the analogous process given for Example 12 except here Moiety A-di-fert butyl ester was coupled with Peptide resin, followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 13. The HPLC purity of Compound 13 was assessed by Method B2. Mass (LCMS): m / z = 1579.52 (MH, *), Calculated Mass= 4741.548; HPLC Purity: 96.5 9% (Method B2), RT=14.76 min. Example 19: Synthesis of Compound 14 The parent peptide was synthesized by solid-phase method. The starting resin used for synthesis was Fmoc-Rink amide resin. Selectively de-blocking of Fmoc protected amino group of rink amide resin using piperidine followed by coupling with Fmoc- Lys(IVDde)-OH with the Rink amide resin. The coupling was performed by using DIPC- HOB to yield Fmoc- Lys(IVDde)-Rink amide Resin, this completes one cycle. Acetic anhydride and diisopropylethyl amine / pyridine was used to terminate / cap the uncoupled amino groups at the end of every amino acid coupling. Selective de-blocking Fmoc of amino group of Fmoc- Lys(IVDde)-Rink amide Resin using piperidine, then coupling with second amino acid ie., Fmoc-Ser(tBu)-OH using HOBt and DIPC yielded Fmoc-Ser(tBu)- Lys(IVDde)-rink amide Resin. This completes 2™ cycle. As stated earlier Acetic anhydride and diisopropylethyl amine / pyridine was used to terminate the uncoupled amino groups after amino acid coupling. The above 3 steps, i.e., deblocking of Fmoc- protection of amino acid attached to the resin, coupling of next amino acid residue in sequence with Fmoc-protected amino group and selective Capping, were repeated for remaining 38 amino acid residues. The side chain of the Fmoc-protected amino acids used were protected orthogonally, e.g., hydroxyl group of Serine, Tyrosine or Threonine were protected with tert-butyl(-tBu) group, amino group of Lysine was protected with tert-butyloxycarbonyl (-Boc) and (4,4-dimethyl-2,6- dioxocyclohex-1-ylidene)-3-methylbutyl (IVDde) group respectively and carboxylic acid groups of aspartic acid or glutamic acid were protected with —tBu group, amide group of glutamine and asparagine were protected with trityl (-Trt) group. The above mentioned three steps, i.e, selective capping, deblocking and then coupling with next Fmoc protected amino acid were performed to get Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Tyr(tBu)-Leu-Glu(OtBu)-Lys(Boc)-Ile-Ala- Ala-Gln(Trt)-Glu(OtBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide resin. De-blocking of Fmoc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)- Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Tyr(tBu)-Leu-Glu(OtBu)-Lys(Boc)-Ile-Ala- Ala-Gln(Trt)-Glu(OtBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser(tBu)- Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide resin. using piperidine followed by Boc protection of Peptide resin using Boc anhydride to yield Boc-Tyr(tBu)- Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile- Tyr(tBu)-Leu-Glu(OtBu)-Lys(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(OtBu)-Phe-Val-Asn(Trt)- Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)- Lys(IVDde)-Rink amide resin. De-protection of IVDde group of peptide resin using Hydrazine hydrate followed by coupling of moiety B-di-fert butyl ester was performed by using diisopropylcarbodiimide, N-hydroxybenzotriazole (DIPC-HOBt) as coupling reagent in presence of which vielded compound 14 resin , Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)- Tyr(tBu)-Ser(tBu)-Ile- Tyr(tBu)-Leu-Glu(OtBu)-Lys(Boc)-Ile-Ala-Ala-Gln(Trt)- Glu(OtBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala- Pro-Pro-Pro-Ser(tBu)-Lys(NH moiety B-di-fert butyl ester)-Rink amide resin cleavage and de-protection using trifluoroacetic acid with ethane-1,2-dithiol and triisopropylsilane followed by purification through preparative HPLC resulted in Compound 14. The HPLC purity of Compound 14 was assessed by Method B53. Mass (LCMS): m / z = 993.06 (MHs >), Calculated Mass= 4960.26; HPLC Purity: 95.8 9% (Method B5), RT=28,308 min, Example 20: Synthesis of Compound 15 Compound 15 was prepared by solid phase method as per the analogous process given for Example 19, wherein for Compound 15 Fmoc-Ser(OMe)-OH was used at position 13 instead of Fmoc-Tyr(tBu) to get Fmoc-Tyr(tBu)-Aib—Glu(OtBu)-Gly-Thr(tBu)-Phe- Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ser(OMe)-Leu-Glu(OtBu)- Lys(Boc)-Ile-Ala-Ala-Gln(Trt)-Glu(OtBu)-Phe-Val-Asn(Trt)-Trp-Leu-Leu-Ala-Gly-Gly- Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(IVDde)-Rink amide resin. Then coupling with Moiety B-di-fert butyl ester followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 15. The HPLC purity of Compound 15 was assessed by Method B4. Mass (LCMS): m / z= 980.77(MHs >), Calculated Mass= 4898.8; HPLC Purity: 94 % (Method B4), RT=41.5 min. Example 21: Synthesis of Compound 16 Compound 16 was prepared by solid phase method as per the analogous process given for Example 16 except here Moiety D-di-fert butyl ester was coupled with Peptide resin, followed by cleavage, de protection and preparative purification using HPLC resulted in Compound 16. The HPLC purity of Compound 16 was assessed by Method B2. Mass (LCMS): m / z = 1243.60 (MHs **), Calculated Mass= 4970.37; HPLC Purity: 97.5 % (Method B2), RT=19.183 min. Biological studies: Example 22: Reduction of HbAlc in db / db type 2 diabetic mice after chronic treatment The effect of Compound 2 on %HbAlc, Insulin, Triglycerides levels, food consumption and body weight was studied on mice. This study was performed in a type 2 diabetic mouse (db / db) model. The animals were divided into 6 treatment groups (n=8 per group) - a diabetic control group, Compound 2 (4.5nM / kg, 9nM / kg and 18nM / kg), and Tirzepatide (90nM / kg and 180nM / kg) treatment group. All the treatments were injected subcutaneously every third day for 10 doses (q3d*10). %HbAlc, Insulin, Triglycerides levels were measured on Day 0, day 14 and day 28. Cumulative food intake from day 0-28 and %Change in body weight compared to day 0 was calculated on day 28. Results are provided in Table 3. Table 3: Effect on HbAlc, Insulin, Triglycerides, food consumption and body wt. A%HbAlc vs. DC | tn Insulin (ng / mL) | Weight (%) Food Ireatment | Day 29 (mg / dL) Day 28 Day 28vs. | Consumpt ‘Groups Rees SE Day 28 Wha ad Ra Fo cae ds. AF ay ey ai wy Day 28 Mean + SD PEyIs Mean + SD ply 2 RAY Mean + SD Trigiyeerides Body Cumulative A%HbALC vs. DC | Insulin (ng / mL) | Weight (%) Food | pg | Day 29 nan Day 28 Day28vs. | Consumption Suk Mean + SD ay Dp Mean + SD Baseline Day 0-28 @=H) ean + Mean +SD | Mean +SD [Day14 [Day28 |Dayi4 [Day28 [Dayl4 [Day28 [Day28 Day 28 Diabetic 4041 [4503+ | 19811 | 1674 Control | 0 0 o bio” | toss | 20218 [20252140 | Compound we eee | 21874 208.9 + 3475+ | 33.44% . we 2, -2.43 | -3.64° i i - = | “7043.2 | 1124 +63 | 4.5nM / kg 56.2 62.7 13.16 17.67 Compound ve ve | 1698+ | 147.4% 6963+ | 5387+ | 89% 1118 + 2.90 4.19’ wr ee a - aot BS 2, 9nM / kg 44.1 16.3 22.42% | 17.27 16 5.1 Compound 3.04% | 4250 1724+ 1443 + 7509+ [7693+ 93 + 895+ 2, 18nM / kg 40.4 20.0" 37.48" | 12.90" | 6.6" as Tirzepatide aes vee | 168.7% 167.4 + 6523+ [5232+ 119.1 + Tirzepatide | , on | ogee | 14342 | 143% | TLT7% | 60.9% | _ oe om 150g | 2 37 | SIE GFF | trae iene | s8232 | 0a234 | For %HbA 1c, Insulin and Triglyceride Data: Two way ANOVA followed by Bonferroni's post test, where *=p<0.05, #*=p<0.01, *+*=p<0,001 vs Diabetic Control; #=p<0.05, ##=p<0.01, ###=p<0.001 vs Tirzepatide at 90 nM / kg For Body weight change and Cumulative food consumption Data: One way ANOVA followed by Bonferroni's post test, where *=p<0.05, ¥*¥=p<0.01, ¥**¥=p<0,001 vs Diabetic Control As evident from the results, Compound 2 at a dose of 4.5, 9 and 18 nM / kg showed statistically significant change in HbA I¢ when compared to the diabetic control both on day 14 and on 28% day. The reduction in HbA lc for Compound 2 exceeded the change showed by tirzepatide at 90 nM / kg dose. A similar effect was seen for Compound 2 on insulin levels wherein at a dose of 9 nM / kg it showed a statistically significant increase in insulin levels when compared to the diabetic control group on day 14. The increase in insulin level was maintained even on day 28. In comparison, tirzepatide at 10 times greater dose (90 nM / kg) showed an equivalent effect on insulin levels. Also, the effect on insulin level shown by Compound 2 at a dose of 18 nM / kg was surprising found to be equivalent to the effect shown by tirzepatide at a dose of 180 nM / kg. The insulin level of Compound 2 at 18 nM was maintained with similar level both on days 14 and 28, however, with tirzepatide treatments it was observed that the insulin level on day 28 tended to be slightly lower than on day 14. Compound 2 at a dose of 4.5, 9 and 18 nM / kg showed statistically significant decrease in body weight when compared to the diabetic control group on day 28. Surprisingly, the effect of Compound 2 on body weight reduction was superior to the effect shown by tirzepatide at a dose of 180 nM / kg (20 times greater dose). Compound 2 at the studied dose (4.5, 9 and 18 nm / kg) also showed statistically significant reduction in cumulative food consumption when compared to the diabetic control group during the course of the study. Surprisingly, the effect on food consumption for Compound 2 was equivalent to the effect shown by tirzepatide at a dose which was10 times the dose of Compound 2. Similarly, Compound 2 at a dose of 4.5, 9 and 18 nM / kg showed statistically significant lowering of triglycerides when compared to the diabetic control group. The effect was maintained with slight improvement on day 28. The efficacy of Compound 2 on lowering of triglycerides level was surprisingly found to be similar to the efficacy shown by tirzepatide at about 20 times the dose of Compound 2. While looking at the effect of Compound 2 on reduction on HbA lc and triglycerides levels it was surprisingly observed that the effect improved on day 28 as compared to day 14. For instance, reduction in HbA Ic at 9 nM / kg and 18 nM / kg dose on day 29 was more than 40 % than the reduction on day 14. In comparison, tirzepatide at 180 nM / kg dose showed minimal improvement in HbA l¢ reduction from day 14 to day 28. Example 23: cAMP Assay In-vitro potency determination was performed using cAMP assay. G protein coupled receptor (GPCR) activation following ligand binding initiates a series of second messenger cascades that results in a cellular response. Signaling by the GLP-1R and GIP-R involves activation of adenylate cyclase and cAMP production. Cellular cAMP production was determined using the cAMP Hunter™ eXpress GPCR Assay (Eurofins DiscoveRx). In cellular cAMP assays, Compound 2 had a half-maximal effective concentration of 4.1 nM on GLP-1R-expressing cells vs about 6.86 nM for Tirzepatide with a Tirzepatide / Compound 2 ratio of 1.68. Also half-maximal effective concentration of Compound 2 was 2.3 nM on GIPR-expressing cells vs 1.89 nM for Tirzepatide with a Tirzepatide / Compound 2 ratio of 0.81. These results demonstrate that the representative Compound 2 is a potent inhibitor of both GLP-1 and GIP receptor. Example 24: Reduction in blood glucose and effect on body weight & food intake The effect of Compounds of present invention on blood glucose was studied on mice. This study was performed in a type 2 diabetic mouse (db / db) model. The animals were divided into 8 treatment groups (n=6 per group) - a diabetic control group, Compound 2 to Compound 7 (3 nM / kg) and a Tirzepatide (10 nM / kg) treatment group. Compound 1 (6 nM / kg) and Compound 2 (6 nM / kg) was compared with Tirzepatide (59 nM / kg) in a separate study (treatment n=5). Baseline blood glucose was measured from all the animals. All animals were administered with its respective test item subcutaneously. Blood glucose was measured at 4hr, 12 hr, 24 hr, 48 hr, 72hr and 96hr post treatment. Delta blood glucose (mM) was calculated. Results are provided in Table 4. Similarly body weight changes and cumulative food consumption was measured at 96 hr post treatment. The results are provided in Table 5 below. Table 4: Effect on blood glucose Treatment Groups n=6 Delta Blood Glucose (mM), Mean (SD. 4hr 12hr 24hr 48hr 72hr 96hr 34 4.6 438 4.6 49 5.1 Control £26 $2.1 £2; £2.6 £2.5 2.5 126 -10.6 83 73 4.7 03 2@3nM | (GRE) | (9H | LRRRF | @25)0H% | ad 2porr | @34)* 3@3nM CER) hk 4.6) +X £23 *2.7 3.1 2.9 4@ 3nM 2.4% £25) +3 £2.8 6.1 E29) 2.5 0.6 03 19 26 S@3nM | @3.6 4TH | (343.7 £5.9 £5.9 3.7 6.1 13 24 17 39 6@3nM | (£2.8)4*¢ | (E2.9)k*x | (#53)% +34 £5.6 £2.8 7@ 30M ALTO | A DRE | ARM | @2 RFK | 1] £2.7 @ 100M 3H | GARE | GAS | @3 SRE | dg Ske (£3. )%* Treatment Groups n=5 0.6 0.6 0.6 0.2 18 0.8 Control 1.3 1.7 2.2 2.1 1.7 2.6 127 BEX] “111 53 0.1 0.1 1 @6nM | F2.8)%*+ | @5.3)%% | @a.5kek | 28 £10 £1.2 L44%ax -18.0%*+ SL6.OF x | gonkk 0.1 2.1 2 @6nM | (x6.4 £2.7 £17 £3.4 233 2.1 Tirzepatide | -11.8 17.7 149 8.1 32 02 @59nM | 4. | ade | @30)0er | @35)x¢ £3.8 £2.5 Two way ANOVA followed by Bonferroni's post test, where *=p<0.05, **=p<0.01, **¥=p<0.001 vs Diabetic Control Table 5: Effect on body weight and food consumption ICumulative Food Intake (g) 0-96| Body Weight Change (%) 96 hr. hr frreatment Groups (n=6) Mean SD Mean SD ! Mean SD Mean SD Diabetic Control 43 18 222 37 MK 13 14. 6%%* 1.0 22 kkk 06 21.9 4.5 27 3ekk 14 205 4.1 «0.5% 13 24.7 12 a3 THER 2 19.1* 34 01 54 209 73 Compound 2 @3nM / kg fluid 17 14.6%** 1.0 25 0.6 219 45 25 14 20.5 4.1 0.5% 12 24.7 12 370% 2 19.1* 34 0.1 54 209 73 34rex 18 13.3% 13 ! Diabetic Control 0.7 08 21.0 4.0 0.1% 18 19.8% 38 — —_ —_ se —_— 0.1% 18 19.8% 38 -0.9 08 182 15 2.8%* 0.6 15.9 57 One way ANOVA followed by Dunnett's posttest, where *=p<0.05, **=p<0.01, #**=p<0.001 vs, Diabetic Control The effect of Compound 2 and Compound 7 on Blood Glucose was further studied on mice at a dose of 10 nM / kg and 30 nM / kg, respectively, wherein blood glucose was measured at 4hr, 8hr, 12hr, 24hr, 48hr and 72 hr post treatment and compared with tirzepatide (90 nM / kg). The results are provided below in Table 6. Similarly body weight changes and cumulative food consumption was measured at 72 hr post treatment. The results are provided in Table 7 below. Table 6: Effect of Compound 2 & 7 on blood glucose Treatment Groups n=§ —t- n= Delta Blood Glucose (mM), MeanSD. 4hr hr 12h 24hr 72hr Diabetic -1.4 05 -0.9 0.8 L5 Control 4.35 4.73 3.42 £2.98 1.31 #237) @10 nM / kg £5.21)" | 5.45)" £5.56)" 4.01)" £3.74)" | @3.64)* @30 nM / kg £5.53)" | 4.58)" 4.05)" £6.30)" £5.99)" | (0.63) @90 nM / kg +4.38)"" | 3.86)" 3.96)" £2.73)" 4.28)" | (4350 Two way ANOVA followed by Bonferroni's posttest, where *=p<0.05, **=p<0.01, ***=p<0.001 vs Diabetic Control Table 7: Effect of Compound 2 & 7 on body weight and food consumption Cumulative Food Consumption veBody | Testment CH fuse wt. change 72hr. vs. Ohr. 0-700 @® Mean SD Mean SD Mean SD Mean SD Diabetic Control 36 1.9 18.3 34 JT JERR 19 8 4kkH a" Compound 2 @10 nM / kg 7 xe 19 8 4Hxk 27 3.70% 23 8.74x+ 04 6.744 = 8 [++ 43 One way ANOVA followed by Dunnett's posttest, where *=p<0.05, **=p<0.01, ***=p<0,001 vs. Diabetic Control The results demonstrate that the compounds of present invention can effectively reduce the blood glucose levels in T2D. The results also demonstrate that the compounds of present invention are effective for a long duration. It is surprising to see that the effect of Compound 2 on blood glucose reduction was similar to the effect shown by tirzepatide at a dose of about 9 times higher than the Compound 2 dose. It was also surprising that the efficacy was maintained for 72 hrs. Similarly, the compounds showed a statistically significant reduction in food intake and body weight. In a separate study, the effects of compound 2, 8, 9 and 10 on blood glucose, food intake and body weight were studied in mice. This study was performed in a type 2 diabetic mouse (db / db) model. The animals were divided into 5 treatment groups (n=6)- a diabetic control group, Compound 2 (10nM / kg), Compound 8 (10nM / kg), Compound 9 (10nM / kg) and Compound 10 (10nM / kg). Baseline blood glucose was measured from all the animals. All the animals were administered with test items subcutaneously. Blood glucose was measured at 4hr, 12hr, 24hr, 48hr, 72hr and 96hr post treatment. Delta blood glucose (mM) was calculated. The results are shown in Table 8. Body weight changes and cumulative food consumption was measured at 96 hr post treatment. The results are shown in Table 9. Similarly the effect of Compounds 11-15 on blood glucose, food intake and body weight was studied in a separate study except for Compound 13. The results are shown in Table § (effect on blood glucose) and Table 9 (effect on body weight and food consumption). Table 8: Effect of Compounds 8,9, 10, 2, 11, 12, 13, 14, 15 and 16 on blood glucose Delta Blood Glucose (mM), Mean(+SD) 4hr 12 hr 24hr 48hr T2hr Lele DIUM OTE DC AIL) ta (aut). | Tissuanet Group [opr ahr 12hr 24hr 48hr | 72hr | 96hr fw Diabetic Control | 0.0 1.1 12 08 7] 27 2.7 43.0 £18 42.3 2.0 +08) | (+23 Compound 8, 00 | -T.6%*% | -83%*% | 76% | 33% | 09 13 10nM / kg / s.c / single | 2.9) (5.5) @53) | @3.0) | @0) |@21) Aoine Diabetic Control 0.0 L1 1.2 0.8 22 2.7 2.7 | 3.0 1.8 #23 (2.0; 0.8 +23 Compound 8, 0.0 =T.6%*% -8.3%wr =7.6%%% =3.3%* -0.9 13 10nM / kg / s.c / single | 2.9) (55) (#5.3) 3.0) #10) | (#2.1) dose #32) | 5 | #2) 0.0 2.5 | &7) | #62) 0.0 1.7) | 43) | #26) 1.0 46 = 28 | 83 | 45 56 0.0 0.0 0.0 ALLL Horr 8, rrr 39 |! 48 34) | FH | ®®5H | 2) Compound 9, 0.0 -11.3* =12.3%%% -3.2 0.7 0.1 1.9 10nM / kg / s.c / single | (#32) 4.5) #32) | 2.7) | 2.0) 2.7) dose Compound 10, 0.0 BORER | 10 8HRx | LT gRRE 0.6 05 14 100M / kg / s.c / single | @25 | @57 | @62) | en | 3.5) #34) dose Compound 2, 0.0 SL3ARER | LL] TRRR | LB 2RRR £.0%* -2.8 0.6 Ton kgs csingle | @1.7) @3) | #26) | @27) | 24) | 09) dose Treatment Group n=6 " x Lo 4.6 28 53 45 56 Diabetic Control | g9 | 33) | @3n | @o | ¢e | ess — Compound 11, 10nM / kg / s.c / single | SLOS*RE | LLL2XRX | 14.6%R% | GARR | 2 gHRX 11 dose 0.0 3.6, 2.7, 4.2 0.9; $17 +2.8 Compound 13 0.0 ST THAR -5.6%*% Brrr 3.9 4.5 72 10nM / kg / s.cisingle | Ba | 0 | @) | @ | #17) | 2.9) dose Treatment Group n=5 Diabetic Control 0.0 0.2 2.2 L7 25 3.6 7.0 paras A gt | Ee Vou | aT Tale #28) | #29 | (#3) 0.0 20.1 21 07 , 12 , 10 1a Diabetic Control 0.0 0.2 22 17 2.5 3.6 7.0 $2.7 #33 3.1 $24) | 340) | @L7 Compound 16 00 | -L44r** | 12.17% | C108%*% | 4.9% | 08 | 0.7% 10nM / kg / s.c / single | 28) | @29) | ®3) | @22) | @26 |ED dose Treatment Group n=5, Tait 0.0 0.1 21 0.7 12 1.0 11 Diabetic Control | (50) | (+1 17, 4,1 £18) | #22) | @23 Compound 12, , 00 | -142%%x | 130% | gore | ssc | 20 17 a 0.0) | @52) 6.6) | 42) | @3) | 4) | @ Compound 14, ) 00 | -163%%% | 13.48% | 96nnn | 9onen | 590 | 06 JoMegnaliinge @00) | @2) | @9 | @6 | @D | @9 | EL) Compound 15, ” 00 | -13.6%%% | 115% | 59% 27 0 11 ImMigss / mage @0.0) | 4) | @an | © | els | @ |e *p<0.05, ¥¥p<0.,01, ***p<0,001 vs Diabetic Control; Two way ANOVA followed by Bonferroni's post-test. Table 9: Effect of Compounds 8, 9, 10, 2, 11, 12, 14 and 15 on body weight and food consumption ‘Cumulative food Intake (g) | Body Wt. Change (%) 96hr, | fet ARTES 47 vs. Baseline I 96hr. vs. Baseline [Treatment Groups (n=6) Mean SD Mean SD 4.1 35 258 49 200% | 0 6 | 16.6%%* | 4. 8 — — — — [Diabetic Control 41 35 a... Compound 8, | 10nM / kg / s.c / single dose Sa | 4 | gore id Compound 9, 10nM / kg / s.c / single dose ol 1 ne i Compound 10, = 2H 0.9 0.8 4 2kkx | 3 | 12 3%%x | 23 14 05 246 4.0 ase | 16 | ae | 34 18 1.0 208 1.2 “31H | 0.9 | 15.21% | 0.7 4 [rx | 11 | 12.38% | 16 10nM / kg / s.c / single dose Compound 2, jo. | wr | 1L0nM / kg / s.c / single dose 42 | zt 123 2 Treatment Groups (n=6, r— [Diabetic Control 1.4 0.5 24.6 4.0 Compound 11, _ | wk | 10nM / kg / s.c / single dose +5 18 St x4 Treatment Groups (n=5) [Diabetic Control 18 1.0 298 1.2 Compound 12, J | — | 10nM / kg / s.c / single dose 3 | 03 152 27 Compound 14, so | . | 1L0nM / kg / s.c / single dose Ad | i vs JE Compound 15, to ot 10nM / kg / s.c / single dose 3.6 03 14.5 0.2 LonM / kgis.cisingle dose, 5" PY | law 22 *p<0.05, **p<0.01, ***p<0.001 vs, Diabetic Control; One way ANOVA followed by Dunnett's post test. Compound 2, Compound 8, Compound 9, Compound 10, Compound 11 and Compound 14 showed statistically significant blood glucose reduction post treatment. Also statistically significant reduction in food intake and body weight was observed compared to diabetic control. The results presented above demonstrate that the compounds of present invention are potent inhibitors of GLP-1 and GIP receptors and can be effective in treatment of type 2 diabetes, diabetes with obesity, obesity and hyperlipidemia.

Claims

Claims 1. A polypeptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence: Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-Xaal5-K-I-A-Xaa19-X3-Xaa21-F-V-Xaa24-W-L-X4- A-G-G-P-S-S-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 1) Wherein X1 is Aib, Ser(OMe) or (D)Ser(OMe); X2 is Tyr, Ser(OMe), (D)Ser(OMe) or Aib; X3 is Gln or Lys; wherein, when X3 is Lys, the side chain amino (€ amino) group of Lys is acylated with a moiety: —U-W-YoZ wherein U is ~C(0)-CHz-O-(CHz)2-O-(CH:2).-NH-} wherein } is the point of attachment with group W; W is selected from a group consisting of —C(0)-NH-(CH:),-NH-], —~C(0)-C(CHs)2-NH-] and —C(0)-CH2-0-(CHz)2-0-(CHz)2-NH-], wherein p is 3 or 4 and wherein ] is the point of attachment with group Y; Y is-C(0)-(CH2)2-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is -C(0)-(CH2)»-COOH or —-C(0)-(CHa)s-CHs wherein n is an integer from 14 to 20; and with a proviso that when X3 is Lys and X2 is Aib, then W is not -C(0)-CHz-0-(CHa)2- 0-(CH2)2-NH-]; X4 is Leu, Ile or Glu; X35 is absent, Arg or Lys; wherein, when X5 is Lys, the side chain amino (€ amino) group of Lys is acylated with a moiety: Ly-w-y-Z' wherein U’ is —C(0)-CH2-0-(CHz)2-0-(CH2)2-NH-} wherein } is the point of attachment with group W’; W’ is selected from a group consisting of ~C(0)-NH-(CHa)q-NH-], -C(0)-C(CHs)2-NH-] and —C(0)-CH2-0-(CHz)2-0-(CHz)2-NH-], wherein q is 3 or 4 and wherein ] is the point of attachment with group Y’; Y’ is-C(0)-(CHa):-CH(COOH)NH-- and -- is the point of attachment with the group Z’; Z’ is -C(0)~(CH2)n-COOH or —C(0)~(CH2)m-CHs wherein m is an integer from 14 to 20; X6 is absent or Lys; X7 is absent or Lys; X8 is absent or Lys; X9 is absent or Lys: X10 is absent or Lys; X11 is absent or Lys; Xaal5 is Asp or Glu; Xaal9 is Gln or Ala; Xaa2l is Ala or Glu; Xaa24 is Gln or Asn; wherein the acid group of the C terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide; and with a proviso at least one of X3 and X5 is Lys.

2. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is Aib.

3. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein X2 is Aib.

4. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 and X2 are both Aib. 5 The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is Aib and X2 is Ser(OMe) or (D)Ser(OMe).

6. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is Ser(OMe) or (D)Ser(OMe) and X2 is Aib.

7. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein X4 is Ile.

8. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein X35 is Arg.

9. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, wherein X1 is Aib and X2 is Tyr.

10. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 5, comprising an amino acid sequence: Y-Aib-E-G-T-F-T-S-D-Y-S-I-Ser(OMe)-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-X4-A-G- G-P-S-§-G-A-P-P-P-S-X5-X6-X7-X8-X9-X10-X11 (Seq. ID 2).

11. The polypeptide or pharmaceutically acceptable salt thereof according to claim 10, wherein X4 is Ile.

12. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-2 comprising an amino acid sequence: Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-X4-A-G-G-P-S-S- G-A-P-P-P-S (Seq. ID 3) wherein X1 is Aib; X2 is Ser(OMe) or Aib; X4 is Ile or Glu.

13. The polypeptide or pharmaceutically acceptable salt thereof according to claim 12, wherein X2 is Aib and X4 is Ile.

14. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, comprising an amino acid sequence: Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-Q-X3-A-F-V-Q-W-L-Ile-A-G-G-P-S- S-G-A-P-P-P-§ (Seq. ID 4); wherein, X3 is Lys and acetylated with the moiety {-U-W-Y-Z and W is selected from a group consisting of —C(0)-NH-(CH2)p-NH-] or —C(0)-C(CHs)2-NH-] wherein ] is the point of attachment with group Y and p is 3 or 4.

15. The polypeptide or pharmaceutically acceptable salt thereof according to claim 1, comprising an amino acid sequence selected from the group consisting of: i) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH2 (SEQ ID NO 5); ii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tvr Ser Ile D-Ser-(OMe) Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser- NH: (SEQ ID NO 9); iii) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser- NH: (SEQ ID NO 10); iv) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Arg (SEQ IDNO 11); v) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys- NH: (SEQ ID NO 12); vi) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Ser(OMe) Leu Glu Lys Ile Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys-NH: (SEQ ID NO 13); vii) Tyr D-Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser- NH: (SEQ ID NO 6): and viii) Tyr Ser(OMe) Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Aib Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser- NH: (SEQ IDNO 7).

16. The polypeptide of any one of the claims 1-11, wherein X5, X6, X7, X8, X9, X10 and X11 are all absent.

17. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein W is —-C(Q)-C(CH3)2-NH-].

18. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein W is —C(0)-NH-(CHz)p-NH-] and p is 3 or 4.

19. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein W is —C(0)-NH-(CH2)4-NH-].

20. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-2, 5, 7-11 and 15-16, wherein W is —C(0)-CH2-0-(CHz)2-0-(CHz)2-NH-].

21. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein Z is —C(O)-(CH2)o-COOH and n is 16 or 18.

22. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein W is —~C(0)-NH-(CH:)+-NH-], Z is -C(0)-(CH2)»-COOH and n is 18.

23. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein W is —C(0)-C(CHs)2-NH-], Z is -C(0)-(CH2)--COOH and n is 18.

24. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-2, 5-12 and 15-16, wherein W is —-C(0)-CH2-0-(CHz):-0-(CH2)2-NH-], Z is —C(0)-(CH2)s-COOH and n is 16.

25. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-2, 5-12 and 15-16, wherein W is —C(Q)-CH2-0-(CHz)2-0-(CH2)2-NH-], Z is —C(0)-(CH2)s-COOH and n is 18.

26. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W’ is —C(0)-C(CHz)2-NH-].

27. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W’ is -C(O)-NH-(CH:)q-NH-] and q is 3 or 4.

28. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W’ is —-C(O)-NH-(CH2)s-NH-].

29. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W’ is -C(0)-CH:-0-(CH2)2-0-(CHz)2-NH-].

30. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 135, wherein Z* is —C(0)-(CH2)m-COOH and m is 16 or 18.

31. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W’ is —-C(0)-NH-(CH2)+-NH-], Z’ is —C(0)-(CH2)m- COOHand mis 18.

32. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W* is ~C(0)-C(CH3)2-NH-], Z’ is -C(0)-(CH2)a-COOH andmis 18.

33. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W* is ~C(0)-CH2-0-(CHz)2-O-(CH2)2-NH-], Z’ is -C(0)- (CH2)m-COOH and m is 16.

34. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-7, 9-11 and 15, wherein W is —C(0)-CHz-O-(CH2)2-0-(CHz2)2-NH-], Z’ is -C(0)- (CH2)m-COOH and m is 18.

35. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-34, wherein -U-W-Y-Z and / or -U’-W*-Y"-Z" is selected from the group consisting of: pg NCA Moiety A; oN 7 Anny or © To 0, wd HON x yt Moiety B; Hoe h. Lonny © — NH oxy eaten C | vo Nw - Moiety C; 1 AAAS © o os" romp Aono A o | Moiety D; and HO. EN 1 AAAS O° o oo Oo Moiety E oS olety 0 AAAS | o 0 36. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1- 35 wherein the C terminal amino acid is amidated as a C-terminal primary amide.

37. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-35, wherein the acid group of the C terminal amino acid is a free carboxylic acid.

38. A polypeptide or pharmaceutically acceptable salt thereof, selected from the group consisting of’ Compound 1: ug W wh Jeorersoverd Finca JAF GW LA GPEC APP PENH, 1] Moisty a= Compound 2 Hoo a wh feerrrsorei Lowa, JAF OWLIAGGR 8 Sea PSN, 1 Moety B=" Compound 3 H voswovnzorrrsovsil Local Larvaniimcerssarsrosim, 1 Moiety pH Compound 4 veuoun ec trrsovsii Joka HAF QWLIAGCGCPS5CAPPAENH, 3 Moity 8- Compound 6 H H wi Learersovsiommomioninat bar vaniirsorsscarra 2 Noisy BV Compound 7 H wi, JearersovsisaomLoxinal JAF VQ WAAC PES C AREA, 1 Moiety gM Compound 8 H Woo wi Feorrrsonsid I iorime A JAF aWLIAG CRE ECAPPP SNH, 1 Moiety eH Compound 9 HQ H WH Learersoveismomn nina frrvewiinsorssansrrsm, Ro Molety & Compound 10 H H bo Wolo! Compound 11 Ho9 ° vel Jearersovsi a JAF VQWLIA-GCGPESGAPPPER 1 Maiety 8-H Compound 13 uo H ba Jhrvauiiacaresaar eran, 1 Moiety A-N Compound 14 HQ Yo ETAT SDN SIYLEKIAAGEFYNWLLAGCSP S80 APP Po, A 1 woos | and Compound 15 H oH Jean sor SHON LEK IAA GE FUN TLLAG SP 850A ERS J, 1 Moiety a wherein, Moiety A is o ANA o op o OH © o Moiety Bis Q NSW oS o AAAS o Moiety C is o spre dn nd os Sh o AAAS o Moiety D is Q ee a Q He Nw 1 ASSAY oO Land Moiety E is Q oa 0 HO. o ow ° OH oO Oo 39. A pharmaceutical composition comprising a polypeptide or pharmaceutically acceptable salt thereof according to any one of the claims 1-38, and one or more of a carrier, diluent or pharmaceutically acceptable excipient.

40. A polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-38 or a pharmaceutical composition according to claim 39 for use as a medicament.

41. A polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-38 or a pharmaceutical composition according to claim 39 for use in the treatment or prevention of a disease in a patient.

42. A polypeptide or pharmaceutically acceptable salt thereof or a pharmaceutical composition for use according to claim 41, wherein said disease is selected from the group consisting of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers 43. The polypeptide or pharmaceutically acceptable salt thereof or a pharmaceutical composition for use according to claims 40-42 wherein said polypeptide or pharmaceutically acceptable salt thereof or said pharmaceutical composition is provided simultaneously, separately, or sequentially in combination with an effective amount of one or more additional therapeutic agents.

44. A method of treating or preventing hyperglycemia, type 2 diabetes, impaired glucose tolerance, type diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers in a patient, comprising administering to a patient in need thereof, an effective amount of the polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1- 38 45. A method of treating or preventing hyperglycemia, type 2 diabetes, impaired glucose tolerance, type diabetes, obesity, hypertension, hyperlipidemia, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers in a patient, wherein said method comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to claim 39.

46. The method according to any one of claims 44-45, further comprising administering simultaneously, separately, or sequentially in combination with an effective amount of one or more therapeutic agents.

47. The polypeptide or pharmaceutically acceptable salt thereof according to any one of claims 1-38, or composition according to claim 39 for use in the preparation of a medicament for the treatment or prevention of hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atherosclerosis, myocardial infarction, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, alcoholism and gastric ulcers.

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