Glp-1 analog peptides, their use in treating diabetes, as well as a pharmaceutical composition comprising said polypeptides, compounds and a process for preparing a compound

Description

1 / 50 “GLP-1 ANALOG PEPTIDES, USE THEREOF TO TREAT DIABETES, AS WELL AS A PHARMACEUTICAL COMPOSITION COMPRISING SAID POLYPEPTIDES, COMPOUNDS AND A PROCESS FOR PREPARING A COMPOUND” Divided from BR 11 2020 020419 6, deposited on 05 / 04 / 2019 RELATED ORDERS

[001] This application claims the benefit of three Indian provisional applications, namely application numbers IN 201821013109 (filed on April 5, 2018); IN 201821040468 (filed on October 26, 2018) and IN 201821040474 (filed on October 26, 2018), which are incorporated herein by reference. FIELD OF DISSEMINATION

[002] This disclosure refers to novel Glucagon-like Peptide-1 (GLP-1) analogues (7-38) possessing an amino acid sequence with Leu or Ile at the C-terminus. The novel analogues are potent GLP-1 agonists with reduced adverse effects and improved duration of action. This disclosure also refers to acylated derivatives of the novel analogues, which have even greater potency and improved duration of action and are suitable for oral administration. The analogues disclosed in this document are acylated with prolonged moieties, which increase the duration of activity of the compounds. The analogues disclosed in this document may be useful in the treatment of diabetes and obesity. Fundamentals of Disclosure

[003] Glucagon-like peptide-1 (GLP-1) is a hormone that is produced primarily in enteroendocrine L cells of the intestine and is secreted into the bloodstream when food containing fat, protein hydrolysate, and / or glucose enters the duodenum. GLP-1 is derived from cell-specific post-translational processing of the pre-proglucagon gene. Initially, the peptide Petition 870260047674, dated 05 / 19 / 2026, page 18 / 109 2 / 50 GLP-1(1-37) was identified from this processing, but it was the two N-terminal truncated products, GLP-1(7-37)(SEQ ID NO: 1) and GLP-1(7-36)amide, that recognized the pancreatic receptor and were determined to be the active species in vivo. GLP-1 was found to stimulate insulin secretion, thus causing glucose uptake by cells and decreasing serum glucose levels. GLP-1 agonists are available for the treatment of Type 2 Diabetes Mellitus (T2DM) as favored drugs because they are free of hypoglycemia and have a positive weight loss benefit. The endogenous substance, GLP-1(7-37) and GLP-1(7-36)amide, is cleaved by peptidases and therefore has a very short half-life. Efforts have been made to improve performance by developing GLP-1 analogs with improved half-lives.The first drug approved in 2005 was Exenatide, with a twice-daily dosage of 10 mcg, which demonstrated a significant improvement in HbA1c, a marker of glucose control. In addition, Novo Nordisk developed Liraglutide (US Patent No. 6,268,343) (SEQ ID NO: 2) with a daily dosage of 1.8 mg, subcutaneously / day, approved in 2010. Further research and development produced weekly administration products such as Albiglutide developed by GSK and Dulaglutide developed by Eli Lilly. Recently, Semaglutide (International Publication No. WO 2006 / 097537 A2), a GLP-1 analog, was approved by the USFDA. Semaglutide (SEQ ID NO: 3) is marketed under the trade name Ozempic®. It is administered as a subcutaneous injection once a week.

[004] Many attempts to produce GLP-1 analogs with improved potency and duration of action are reported in the literature. U.S. Patent No. 7,291,594 B2 (the U.S. Patent '594) discloses GLP-1 derivatives (7-35) having added several arginine and / or lysine residues to the C-terminus thereof to provide high bioavailability across mucous membranes. The U.S. Patent '594 also discloses that these derivatives can be conferred with resistance to Petition 870260047674, dated 05 / 19 / 2026, p. 19 / 109 3 / 50 dipeptidyl peptidase IV (DPP-IV), replacing amino acid 8 in its GLP-1 amino acid sequence with Ser, or with trypsin resistance by replacing amino acids 26 and 34 with Gln and Asn, respectively.

[005] U.S. Patent No. 7,893,017 B2 (the U.S. Patent '017) discloses an acylated GLP-1 analog wherein the GLP-1 analog is stabilized against DPPIV by modification of at least one amino acid residue at positions 7 and 8 relative to the GLP-1 sequence (7-37) and wherein said acylation is a diacid directly linked to the C-terminal amino acid residue of said GLP-1 analog.

[006] U.S. Patent No. 8,951,959 B2 (the U.S. Patent '959) discloses a DPP-IV resistant GLP-1 (7-37) analog having a non-proteogenic amino acid residue containing a trifluoromethyl group at position 8 relative to the GLP-1 sequence, and is acylated with a moiety comprising two acidic groups to the lysine residue at position 26.

[007] U.S. Patent No. 7,084,243 B2 (the U.S. Patent '243) discloses GLP-1 (7-37) analogs possessing Val or Gly at position 8 relative to the GLP-1 (7-37) sequence as DPP-IV resistant peptides.

[008] International Publication No. WO 2017 / 149070 A1 (WO '070) discloses GLP-1 analogues possessing a Trp in a position corresponding to position 8 of GLP-1 (7-37) and these Trp8 compounds have been shown to be very stable against degradation by DPP-IV.

[009] International Publication No. WO 2004 / 103390A2 (WO '390) discloses that modification at position P'1 (corresponding to position 9 in the case of GLP-1 (7-37)) can produce GLP-1 analogs with significantly reduced susceptibility to enzyme-mediated cleavage (such as DPP-IV) compared to the native substrate, while still maintaining the biological activity of the native substrate. WO '390 also discloses GLP-1 (7-37) analogs possessing a tetrasubstituted C-carbon amino acid (such as tert-leucine) at position 9. Petition 870260047674, dated 05 / 19 / 2026, p. 20 / 109 4 / 50 provides LPG analogs with resistance to DPP-IV degradation.

[010] International Publication No. WO 2015 / 086686 A2 (the publication of WO '686) discloses that incorporation of functionalized alpha-methyl amino acids directly into the main chain of GLP-1 analogs was determined to produce protease-resistant peptides (including DPP-IV resistant).

[011] Several other DPP-IV resistant GLP-1 agonists are disclosed in patent publications, such as International Publications No. WO 2007 / 030519 A2, WO 2004 / 078777 A2, WO 2007 / 039140 A1, WO 2014 / 209886 A1, WO 2012 / 016419 A1, WO 2017 / 211922 A2, WO 2016 / 198544 A1 and WO 2013 / 051938 A2.

[012] Several patent applications disclose extended C-terminal GLP-1 analogs with greater stability and longer duration of action. For example, U.S. Patents Nos. 7,482,321 B2, 9,498,534 B2 and 7,897,566 B2.

[013] Several patent applications disclose acylated GLP-1 analogs in which the GLP-1 analogs are linked to lipophilic substituents optionally via a peptide linker to provide longer duration of action.

[014] U.S. Patent No. 8,603,972 B2 (the U.S. '972) discloses monoacylated derivatives of GLP-1 analogues, wherein the Lys residue at position 37 or 38 of the GLP-1 analogue is acylated.

[015] U.S. Patent Nos. 8,648,041 B2, 9,758,560 B2, 9,006,178 B2, 9,266,940 B2, 9,708,383 B2 and U.S. Patent Application Publication Nos. U.S. 2015 / 0152157 A1, U.S. 2015 / 0133374 A1 disclose diacylated derivatives of LPG-1 analogues.

[016] The Publication of United States Patent Application No. US 2016 / 0200791 A1 discloses triacylated derivatives of GLP-1 analogues.

[017] International Publications No. WO 2016 / 083499 A1, WO 2016 / 097108 A1 and WO 2014 / 202727 A1 discloses acylated LPG-1 analogues in which the Lys residue of LPG-1 analogues is linked to two extended fractions Petition 870260047674, dated 05 / 19 / 2026, p. 21 / 109 5 / 50 through a branched peptide ligand.

[018] International Publications No. WO 2009 / 030771 A1 and WO 2018 / 083335 A1 disclose several acylation (side chain) agents that can be attached to the Lys residue of GLP-1 analogues to provide longer duration of action.

[019] International Publication No. WO 2013 / 186240 A2 discloses exendin-4 peptide analogs having Gly, Ser or functionalized Ser, for example, Ser (OCH3), D-Ser or functionalized D-Ser, for example, D-Ser(OCH3), Aib, Ala, or DAla at position 2 of the exendin-4 amino acid sequence.

[020] Several other GLP-1 analogues are disclosed in patent applications, such as International Publications No. WO 2005 / 027978 A2, WO 1998 / 008871 A1, WO 1999 / 043705 A1, WO 1999 / 043706 A1, WO 1999 / 043707 A1, WO 1999 / 043708 A1, WO 2000 / 034331 A2, WO 2009 / 030771 A1, WO 2011 / 080103 A1, WO 2012 / 140117 A1, WO 2012 / 062803 A1, WO 2012 / 062804 A1, WO 2013 / 037690 A1, WO 2014 / 202727 A1, WO 2015 / 000942 A1, WO 2015 / 022400 A1, WO 2016 / 083499 A1, WO 2016 / 097108 A1 and WO 2017 / 149070 A1.

[021] Nevertheless, there is a need to develop GLP-1 analogues that have ideal desired properties in terms of stability and duration of action. SUMMARY OF THE DISCLOSURE

[022] One aspect of the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib, ; X3 is missing or is Gln; X4 is Glu; Petition 870260047674, dated 05 / 19 / 2026, page 22 / 109 6 / 50 X16éGlu; X24 is a lie; X33 is Leu, D-Leu, D-lle or Ile; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is absent or is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of attachment to the W group; W is absent or is selected from a group consisting of -C(O)-CH2O-(CH2)2-O-(CH2)2-NH-], -C(O)-NH-(CH2)3-4-NH-], -C(O)-C(CH3)2-NH-] and -C(O)-NH\ N—] \— / where ] is the point of connection with the Y group; Y is C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3 where n is an integer from 14 to 20.

[023] The polypeptides in this disclosure are potent GLP-1 agonists with fewer adverse effects. In addition, the polypeptides in this disclosure are stable, have a long duration of action, and are suitable for oral administration. DESCRIPTION OF THE FIGURES

[024] Figure 1A illustrates the preparation of Portion A-OSu (Intermediate 3). Figure 1B illustrates the preparation of Portion A-OSu (Intermediate 3).

[025] Figure 2 illustrates the preparation of Portion C-OSu.

[026] Figure 3 illustrates the preparation of Portion D-OSu.

[027] Figure 4 illustrates the preparation of Portion E-OSu.

[028] Figure 5 illustrates the preparation of Portion F-OSu. Petition 870260047674, dated 05 / 19 / 2026, page 23 / 109 7 / 50

[029] Figures 6A and 6B illustrate the results of an oral glucose tolerance test (OGTT) for Compound 1 in rats; single injection; 1 mg / kg of glucose AUC 0-120 min (Figure 6A = after 22 h, Figure 6B = after 46 hrs).

[030] Figure 7 illustrates the reduction in blood glucose levels in db / db type 2 diabetic mice after chronic treatment with Compound 1.

[031] Figure 8 illustrates the reduction in food intake in db / db mice after treatment with Compound 1.

[032] Figure 9 illustrates the effectiveness of Compound 1 in db / db mice in reducing body weight.

[033] Figure 10 illustrates the reduction in Hb1Ac in db / db mice after treatment with Compound 1. ABBREVIATIONS Aib: 2-aminoisobutyric acid ADO: 8-amino-3,6-dioxooctanoic acid OGTT: Oral glucose tolerance test DIPEA: N,N'-Diisopropylethylamine HOBt: 1-Hydroxybenztriazole DIPC: N,N′-Di-isopropylcarbodiimide HOSu: N-Hydroxysuccinimide IBCF: Isobutyl chloroformate NMM: N-Methylmorpholine THF: Tetrahydrofuran DCM: Dichloromethane DMAP: 4-Dimethylaminopyridine DCC: Dicyclo-hexyl carbodiimide DMAc: Dimethylacetamide DESCRIPTION BY DISCLOSURE Petition 870260047674, dated 19 / 05 / 2026, p. 24 / 109 8 / 50

[034] This disclosure provides a stable, long-acting GLP-1 analog that does not require frequent subcutaneous dosing and is also suitable for oral administration. Surprisingly, the addition of an extra Leu at the C-terminus of the sequence was found to produce peptides with significantly improved potency and duration of action when compared to the source peptide. Peptides with an additional Ile also showed a similar effect of improved potency and duration of action when compared to the source peptide. Furthermore, the disclosure in this document demonstrates fractions that can be attached to peptides that are GLP-1 analogs (7-37) via acylation reaction to produce compounds with significantly improved potency and longer duration of action. The extended fractions of the disclosed compounds have more stable linkages that are less susceptible to cleavage by biological enzymes.Thus, the compounds disclosed in this document are more stable and require less frequent administration, adding to patient compliance. Consequently, in some embodiments, the disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 (SEQ ID NO: 4) where X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib, ; X3 is missing or is Gln; X4 is Glu; X16 is Glu; X24 is Ile; X33 is Leu, D-Leu, D-Ile or Ile; X34 is missing and X21 is Lys in which the side chain amino group (8 amino) of Lys is acylated. Petition 870260047674, dated 05 / 19 / 2026, p. 25 / 109 9 / 50

[035] In some embodiments, X21 can be acylated with the extended fractions reported in U.S. Patents Nos. 6,268,343, 8,951,959 B2, 8,603,972 B2, 8,648,041 B2, 9,758,560 B2, 9,006,178 B2, 9,266,940 B2, 9,708,383 B2 and U.S. Patent Application Publication Nos. US 2015 / 0152157 A1 and US 2015 / 0133374 A1; International Publication Nos. WO 2009 / 030771 A1, WO 2006 / 097537 A2 and WO 2018 / 083335 A1.

[036] In some embodiments, X21 Lys is acylated at its side-chain amino group (8 amino) with a moiety comprising a fatty acid group. The fatty acid group can be linked to X21 Lys via a ligand. Consequently, in some embodiments, the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib ; X3 is missing or it's Gin; X4 is Glu; X16éGlu; X24 is a lie; X33 is Leu, D-Leu, D-lle or Ile; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is absent or is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of attachment to the W group; W is absent or is selected from a group consisting of -C(O)-CH2O-(CH2)2-O-(CH2)2-NH-], -C(O)-NH-(CH2)3-4-NH-], -C(O)-C(CH3)2-NH-] and Petition 870260047674, dated 05 / 19 / 2026, page 26 / 109 10 / 50 -C(O)—NH-ζ N—] \— / where ] is the point of connection with the Y group; Y is C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3 where n is an integer from 14 to 20.

[037] In some embodiments, the amino acid in X2 is selected from Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib.

[038] In some modes X2 is Aib.

[039] In some modes, X3 is absent.

[040] In some forms, X33 is Leu.

[041] In some modes, X33 is a lie.

[042] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is selected from a group consisting of -C(O)-NH-c(O)-nh / n—] (CH2)3-4-NH-], -C(O)-C(CH3)2-NH-] and

[043] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where U and W are both absent and Z is -C(O)-(CH2)n-CH3 where n is the integer 14.

[044] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-].

[045] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: Petition 870260047674, dated 05 / 19 / 2026, p. 27 / 109 11 / 50 {-QTUWYZ where W is -C(O)-C(CH3)2-NH-].

[046] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-NH-(CH2)4-NH-].

[047] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-NH-(CH2)3-NH-].

[048] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ -C(O)—NH-Z N—] whereWé \— /

[049] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Z is -C(O)-(CH2)n-COOH, where n is the integer 16.

[050] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Z is -C(O)-(CH2)n-CH3 where n is an integer 14.

[051] In some sports, X2 is Wing or Aib; X3 is missing; X33 is Leu; U is absent; W is missing; Petition 870260047674, dated 05 / 19 / 2026, p. 28 / 109 12 / 50 Y is -C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; Z is -C(O)-(CH2)n-CH3 where n is the integer 14.

[052] In some embodiments, the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Aib; X3 is missing; X4 is Glu; X16éGlu; X24 is a lie; X33 is Leu; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is-C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of attachment to the W group; W is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], where ] is the attachment point of group Y; Y is C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; Z is -C(O)-(CH2)n-COOH where n is the integer 16.

[053] In some embodiments, the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LPetition 870260047674, dated 05 / 19 / 2026, p. 29 / 109 13 / 50 VRGRG-X33-X34 where X2 is Aib; X3 is missing; X4 is Glu; X16éGlu; X24 is a lie; X33 is Leu; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of connection with the W group; W is -C(O)-C(CH3)2-NH-] where ] is the point of attachment to group Y; Y is C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to the Z group; Z is -C(O)-(CH2)n-COOH where n is the integer 16.

[054] In some embodiments, the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Aib, ; X3 is missing; X4 is Glu; X16éGlu; X24 is a lie; X33 is Leu; Petition 870260047674, dated 05 / 19 / 2026, p. 30 / 109 14 / 50 X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is-C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of attachment to the W group; W is -C(O)-NH-(CH2)3-4-NH-] where ] is the point of attachment to the Y group; Y is C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; Z is -C(O)-(CH2)n-COOH where n is the integer 16.

[055] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-NH-(CH2)4-NH-].

[056] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-NH-(CH2)3-NH-].

[057] In some embodiments, the disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Aib, ; X3 is missing; X4 is Glu; X16éGlu; X24 is a lie; Petition 870260047674, dated 05 / 19 / 2026, page 31 / 109 15 / 50 X33 is Leu; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is-C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of attachment to the W group; W is -C(O)-NH-(CH2)4-NH-], where ] is the attachment point of the Y group; Y is -C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3 where n is an integer from 14 to 20.

[058] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Z is -C(O)-(CH2)n-COOH where n is the integer 16.

[059] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Z is -C(O)-(CH2)n-CH3 where n is the integer 14.

[060] In some embodiments, the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Aib, ; X3 is missing; X4 is Glu; Petition 870260047674, dated 05 / 19 / 2026, p. 32 / 109 16 / 50 X16éGlu; X24 is a lie; X33 is Leu; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Q and T are absent; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of connection with the W group; -C(O)-NH-( n—] W is \— / where ] is a connection point with group Y; Y is -C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; and Z is -C(O)-(CH2)n-COOH where n is the integer 16.

[061] In some embodiments, the present disclosure provides a polypeptide comprising the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 where X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe); X3 is missing; X4 is Glu; X16éGlu; X24 is a lie; X33 is Leu; X34 is missing and X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ Petition 870260047674, dated 05 / 19 / 2026, p. 33 / 109 17 / 50 where Q and T are absent; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-} where} is the point of connection with the W group; W is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-, -C(O)-NH-(CH2)3-4-NH-], -C(O)C(CH3)2-NH-], where ] is a point of attachment to the Y group; Y is -C(O)-(CH2)2-CH(COOH)NH--, where -- is the point of attachment to group Z; and Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3 where n is an integer from 14 to 20.

[062] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where Wé -C(O)-NH-(CH2)3-4-NH-].

[063] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-;

[064] In some embodiments, X21 is Lys in which the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ where W is -C(O)-C(CH3)2-NH-]

[065] In some embodiments, X21 is lipid-modified Lys in which the side-chain amino group (8 amino) is acylated with a {-QTUWYZ} moiety that is represented by the fractions provided in Table 1 _______Table 1: Representative fractions for the {-QTUWY-Z} group__________ Portion Designation Petition 870260047674, dated 05 / 19 / 2026, p. 34 / 109 18 / 50 Portion AH h JHOH°¥'1 οΛ^ / '^^^0” O Portion B O. OH o HO Portion CH 9 JHHO H0YÇ οο¥--'- / ^^ O Portion DH 9 O 7 HOH°¥ 1 ο ^-H^ JOH O^\ / —' X / XZXZxz γ O Portion E Η Η Η OO\ / N. A Μ Λ A yt oH°Y 4 ο Λ A ^OH O^\ / ΧΖ \x^ Ύ O Portion FHH ο γγχNχ^N\ / ^ο^^ O^N.^ OO

[066] In another embodiment, the present disclosure provides a polypeptide according to any of the previous embodiments, which is selected to Petition 870260047674, dated 05 / 19 / 2026, page 35 / 109 19 / 50 from the peptides provided in Table 2: Table 2: Representative polypeptide compounds of the present divulg ação Comp. # Estrutura* Seq ID 1 Η O H ° H-N 11-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-N t1—E-F-l-A-W-L-V-R-G-R-G-L Fração^^ SEQ ID NO: 05 2 ... ________________________ H O H-Ser(OMe)-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A_^]^^IJ_ ^-F-l-A-W-L-V-R-G-R-G-L FraçãcrAJvlH SEQ ID NO:: 06 3 H 0 h 9 H-N IL Q-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-N E-F-l-A-W-L-V-R-G-R-G-L FraçãoA?NH SEQ ID NO: 07 4 Η O H ° H-N 11-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-N J1— E-F-l-A-W-L-V-R-G-R-G-(DLeu) Fração A-NH SEQ ID NO: 08 5 H ? H-S-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-n JJ—E-F-l-A-W-L-V-R-G-R-G-L Fração A -NH SEQ ID NO:: 09 6 H O H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A—N U— E-F-I-A-W-L-V-R-G-R-G-L Fração B ,NH SEQ ID NO: 10 Petição 870260047674, de 19 / 05 / 2026, pág. 36 / 109 20 / 50 7 η 9 η 9 Η—N 11-EGTFTSDVSSYLEGQAAN JJ—EFlAWLVRGRGL Fraction^B^NH SEQ ID ΝΟ:: 05 8 H 9 H ° SEQ HN Jl— EGTFTSDVSSYLEGQAAN J1—EFlAWLVRGRGl ID Fraction^A^NH NO: 11 9 HH SEQ H-(DSer(OMe))-EGTFTSDVSSYLEGQAA—N JJ— EFlAWLVRGRGL ID Fraction A -NH NO: 12 10 H ? SEQ H-(DSer)-EGTFTSDVSSYLEGQAA—N Jl—EFlAWLVRGRGL Fragment ID^^NH NO: 13 11 Η 0 H ° SEQ H—N^JJ—QEGTFTGDVGGYLEGQAA—N K- EFlAWLVRGRG-(DLeu) Fragment IDAJMH NO: 14 12 H ? SEQ HAEGTFTSDVSSYLEGQAan U— EFlAWLVRGRGL ID NO: Fraction^A^NH 10 13 HO HO SEQ H-^IL- EGTFTSDVSSYLEGQAAN jl—efiawlvrgrgl Fraction ID^C^JH -------, _ NO: 05 Petition 870260047674, 05 / 19 / 2026, p. 37 / 1 21 / 50 14 H ? HSEGTFTSDVSSYLEGQAAn 11—efiawlvrgrgl SEQ ID NO:: 09 Fraction C ,NH 15 H 9 H ° H-N'Jl— EGTFTSDVSSYLEGQAAN j1—EFlAWLVRGRGl Fraction^C^NH SEQ ID NO:: 11 16 H 9 H 9 EGTFTSDVSSYLEGQAAN 1·— EFIAWLVRGRGL Fraction^D^NH SEQ ID NO: 05 17 H 9 H 9 EGTFTSDVSSYLEGQAAN 1·—EFIAWLVRGRGL Fraction^NH SEQ ID NO: 05 18 HO HO HN^JL-EGTFTSDVSSYLEGQAAN / — EFIAWLVRGRGL Fraction^F^jh -------, . SEQ ID NO: 05 * Unless otherwise indicated, all amino acids in the structures have an L configuration at the α position. D, when used as a prefix to the amino acid in the sequence, denotes the D configuration of the amino acid. For example, (DSer) denotes that the amino acid Serine in the sequence has a D configuration.

[067] Unless otherwise indicated, the disclosure is intended to cover the L and D isomers of amino acids in the sequences.

[068] Ser(OMe) as described in this document in the disclosure is the amino acid serine with its hydroxyl group methylated and has the following structure. Petition 870260047674, dated 05 / 19 / 2026, p. 38 / 109 22 / 50 OMe THE

[069] The polypeptide sequences mentioned in the disclosure are represented by the single-letter amino acid code as approved by IUPAC.

[070] Q, T, U, W, Y and Z as used in this document to define the acylation moiety of the embodiments of the present disclosure are different from the single-letter amino acid code used to denote the polypeptide sequence.

[071] The polypeptides in this disclosure surprisingly showed a significant reduction in blood glucose when subjected to an oral glucose tolerance test (OGTT) in SD rats. The percentage reduction in blood glucose in SD rats when exposed to oral glucose was significantly lower than the corresponding polypeptides lacking the additional Leu or Ile at position X33.

[072] The present invention is illustrated in detail with reference to the following examples. It is desirable that the example be regarded in all respects as illustrative and is not intended to limit the scope of the claimed invention. EXAMPLES: General Preparation Methods:

[073] The polypeptide compound of the present disclosure can be prepared by methods described below in this document. The process involves two steps, involving the preparation of the linear parent peptide and subsequent fatty acid chain linkage to the parent peptide.

[074] The peptides described in this document can be prepared by chemical synthesis using solid-phase techniques such as those described in G. Barany and RB Merrifield, “The Peptides: Analysis, Synthesis, Biology” Volume 2— Petition 870260047674, dated 05 / 19 / 2026, page 39 / 109 23 / 50 “Special Methods in Peptide Synthesis, Part A”, pp. 3-284, E. Gross and J. Meienhofer, Eds., Academic Press, New York, 1980; and in JM Stewart and JD Young, “SolidPhase Peptide Synthesis”, 2nd Ed., Pierce Chemical Co., Rockford, Ill., 1984. The desired strategy is based on the Fmoc (9-Fluorenylmethyl-oxycarbonyl) group for temporary protection of the α-amino group, in combination with protecting groups such as tert-butyl (-tBu), tert-butyloxycarbonyl (-Boc), trityl (-Trt) groups for temporary protection of amino acid side chains (see, for example, E. Atherton and RC Sheppard, “The Fluorenylmethoxycarbonyl Amino Protect Group”, in “The Peptides: Analysis, Synthesis, Biology” Volume 9-“Special Methods in Peptide Synthesis, Part C”, pp. 1-38, S. Undenfriend and J. Meienhofer, Eds., Academic Press, San Diego, 1987).

[075] Peptides can be synthesized gradually on an insoluble polymeric support (also referred to as a resin) starting from the C-terminus of the peptide. A synthesis is initiated by the attachment of the C-terminal amino acid of the peptide to the resin through the formation of an amide or ester linkage. This allows the eventual release of the resulting peptide as a C-terminal amide or carboxylic acid, respectively.

[076] The C-terminal amino acid and all other amino acids used in the synthesis are required to have their α-amino groups and side-chain functionalities (if present) differentially protected so that the α-amino protecting group can be selectively removed during synthesis. The coupling of an amino acid is performed by activating its carboxyl group as an active ester and reacting it with the unlocked α-amino group of the N-terminal amino acid attached to the resin. The sequence of deprotection and coupling of the α-amino group is repeated until the entire peptide sequence is assembled. The peptide is then released from the resin with concomitant deprotection of the side-chain functionalities, usually in the presence of appropriate scavengers to limit side reactions. The resulting peptide is finally purified by reverse-phase HPLC. Petition 870260047674, dated 05 / 19 / 2026, page 40 / 109 24 / 50

[077] The parent peptide can then be coupled to the fatty acid chain by coupling the activated fatty acid chain with the parent peptide. The fatty acid chain can be produced by well-known methods in organic chemistry. For example, the fatty acid chain can be made using synthetic solid-phase methods that allow the preparation of linear fatty acid chains.

[078] The synthesized linear peptides were purified by preparative HPLC procedure as described below: Preparative HPLC: WATERS 2555 quaternary gradient module (Maximum total flow: 300 mL / min, Maximum pressure: 3000 psi) or Shimadzu LC-8A (Maximum total flow: 150 mL; Maximum pressure: 20 MPa) Column: C18, 10μ Flow rate: 75 mL / min Mobile Phase: For initial purification Mobile Phase A: pH 7.5 Phosphate buffer p Mobile Phase B: Acetonitrile Gradient: 10 to 40% Mobile Phase-B in 300 min. For the second purification: Mobile Phase A: 1% acetic acid in water Mobile Phase B: 1% acetic acid in Acetonitrile:n-Propanol (50:50) Gradient: 15 to 45% Mobile Phase B in 300 min

[079] The final compounds of this disclosure were purified by preparative HPLC procedure as described below: Preparative HPLC: WATERS 2555 quaternary gradient module (Maximum total flow: 300 mL / min, Maximum pressure: 3000 psi) or Shimadzu LC-8A (Maximum total flow: 150 mL, maximum pressure: 20 MPa) Column: C18, 10μ Flow rate: 75 mL / min Petition 870260047674, dated 05 / 19 / 2026, page 41 / 109 25 / 50 Mobile Phase: For first purification For second purification Mobile Phase A Phosphate buffer pH 7.5 1% acetic acid in water Mobile Phase B Acetonitrile 1% acetic acid in Acetonitrile:n-Propanol (50:50) Gradient 10 to 40% Mobile Phase B in 300 min 15 to 45% Mobile Phase B in 300 min

[080] The purity of the compounds in this disclosure was analyzed by RP-HPLC as described below: HPLC Method B1: Column: YMC Pack-Ph (4.6 mm X 150 mm 3μ) Eluent: Mobile Phase A: 0.1% trifluoroacetic acid in water Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile Flow rate: 1.5 mL / min Detection: UV detection at 210 nm Column Temperature: 50 °C Execution Time: 50 min. Gradients: Time Mobile Phase A % Mobile Phase B % 0.01 90 10 35.0 20 80 40.0 20 80 41.0 90 10 50.0 90 10 HPLC Method B2: Column: YMC-Pack Pro C18 (4mm x 250mm, 3μ) Eluent: Mobile Phase A: Buffer: Acetonitrile (900:100) Petition 870260047674, dated 05 / 19 / 2026, page 42 / 109 26 / 50 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: 50 °C Sample Tray Temperature: 8 °C Execution Time: 38 min. Mobile Phase A Time % Mobile Phase B Time % 0 100 0 5 100 0 30 0 100 32 0 100 32.1 100 0 38 100 0 HPLC Method B3: Column: Waters X-Select CSH-C18 (150 mm X 4.6 mm; 2.5 μ) Eluent: Mobile Phase A: Buffer: Acetonitrile (900:100) Mobile phase B: Buffer: Acetonitrile (300:700 Buffer: Potassium dihydrogen orthophosphate in water, pH adjusted to 1.5±0.1 with orthophosphoric acid. Flow rate: 0.9 mL / min Detection: UV detection at 210 nm Column Temperature: 40 °C Sample Tray Temperature: 5 °C ______Running Time: 100 min._____________________________________ Time Mobile Phase A Mobile Phase B 0 50 50 Petition 870260047674, dated 05 / 19 / 2026, page 43 / 109 27 / 50 40 43 57 55 43 57 90 0 100 91 50 50 100 50 50

[081] The compounds in this disclosure were analyzed by LCMS as described below:

[082] Mass spectra were recorded on the LCMS using Waters Acquity® QDa®, Waters Micromass Quattro Micro API, or Thermo Scientific LCQ Fleet™. The test solution was prepared by dissolving an appropriate amount of analyte in diluent to a final concentration of 1 μg / ml to 50 μg / ml, depending on the analyte ionization. The test solution was infused at a rate of approximately 10 μl to 50 μl per minute into the LCMS for 1 min, and mass spectra were recorded in positive or negative Electrospray Ionization (ESI) mode and in an appropriate mass range. Example 1: Preparation of activated fatty acid side chains: 1. Preparation of 18-[[[(1S)-1-carboxy-4-[2-[2-[2-[2-[2-[2-(2,5dioxopyrrolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethylamino]-2-oxo-ethoxy]ethoxy]ethylamino]-4oxo-butyl]amino]-18-oxo-octadecanoic acid (A-OSu Portion, Intermediate-3)

[083] The activated fatty acid side chain, Portion A-OSu, was prepared by solid-phase synthesis using 2-chlorotrityl chloride resin as shown schematically in Figure 1A. 2-[2-(2-Fmocaminoethoxy)ethoxy]acetic acid (Intermediate-1) was linked to the 2-chlorotrityl chloride resin in the presence of N,N'-diisopropylethylamine (DIPEA) which yielded 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid-Resin 2-Cl-Trt. Intermediate-1 can be prepared by coupling 2-[2-(2-aminoethoxy)ethoxy]acetic acid with Fmoc N-hydroxysuccinimidic ester. Alternatively, Intermediate-1 is Petition 870260047674, dated 05 / 19 / 2026, p. 44 / 109 28 / 50 commercially available and can be purchased as such. The Fmoc protecting group was removed by selectively unlocking the amino group of 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid-Resin 2-Cl-Trt using piperidine and the free amino group was then coupled to 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid using 1-hydroxybenztriazole (HOBt) and N,N'-diisopropylcarbodiimide (DIPC) which generated 2-[2-[[[2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid-Resin 2Cl-Trt. The Fmoc group was then removed by selectively unlocking the amino group of 2-[2-[2-[[2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid resin 2-Cl-Trt using piperidine, and the free amino group was then coupled to FmocGlu-OtBu using HOBt and DIPC to obtain 2-[2-[[[2-[2-[2-[[(4S)-4-Fmocamino-5-tert-butoxy-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid resin 2-Cl-Trt.The resulting 2-[2-[2-[[2-[2-[2-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid-Resin 2Cl-Trt was selectively unblocked using piperidine and then coupled to mono-tert-butyl ester of octadecanedioic acid to obtain a 2-intermediate namely [2-[2-[[2-[[2-[2-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo-pentanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid]-Resin 2-Cl-Trt. Intermediate 2 was then cleaved from 2-Cl-Trt resin using trifluoroethanol:DCM (1:1). The resulting compound was then reacted with N-hydroxysuccinimide (HOSu) in the presence of isobutyl chloroformate (IBCF) and N-methylmorpholine (NMM) followed by deprotection with trifluoroacetic acid to generate the title compound (A-OSu portion, intermediate-3). The entire process can also be represented as shown schematically in Figure 1B. 2. Preparation of N-palmitoyl-L-γ-glutamyl succinimide ester (BOSu portion) Petition 870260047674, dated 05 / 19 / 2026, p. 45 / 109 29 / 50 Fraction ty B-OSu

[084] Alpha-tert-butyl ester of L-glutamic acid (H-Glu-OtBu) reacted with palmitic acid in the presence of IBCF and NMM to generate CH3-(CH2)14-C(O)-GluOtBu, which then reacted with HOSu in the presence of IBCF and NMM to generate CH3(CH2)14-C(O)-Glu(OSu)-OtBu, which was then deprotected with trifluoroacetic acid to generate the B-OSu moiety. 3. Preparation of 18-[[[(1S)-1-carboxy-4-[4-[2-[2-[2-(2,5-dioxopyrirolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethylcarbamoylamino]butylamino]-4-oxobutyl]amino]-18-oxo-octadecanoic acid (C-OSu portion)

[085] The activated fatty acid side chain, C-OSu Portion, was prepared using solid-phase synthesis using 2-chlorotritile chloride resin as schematically represented in Figure 2. 2-[2-(2-Fmocaminoethoxy)ethoxy]acetic acid was linked to 2-chlorotritile chloride resin in the presence of DIPEA to generate 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid-Resin 2-Cl-Trt. The Fmoc protecting group was removed by selectively unlocking the amino group using piperidine, and the free amino group was then activated using p-nitrophenylchloroformate in THF and DIPEA, followed by reaction with the butylamine hydrochloride salt of Fmoc-amino in THF:DMac and DIPEA, which generated 2-[2-[2-(4Fmoc-aminobutylcarbamoylamino)ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt.The Fmoc group was removed by selective unlocking using piperidine, and the free amino group was then coupled to Fmoc-Glu-OtBu using HOBt and DIPC, which generated 2-[2-[2-[[[(4-S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]butylcarbamoylamino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt. The resulting 2-[2-[2-[4-[[(4S)-4Fmoc-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]butylcarbamoylamino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt was selectively unlocked using piperidine and then coupled to mono-tert-butyl ester. Petition 870260047674, dated 05 / 19 / 2026, p. 46 / 109 30 / 50 of octadecanedioic acid to obtain the intermediate 2-[2-[2-[4-[[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxopentanoyl]amino]butylcarbamoyl amino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt. The intermediate was then cleaved from Resin 2-Cl-Trt using trifluoroethanol:DCM (1:1) to obtain 2-[2-[2-[4-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxooctadecanoyl)amino]-5-oxo-pentanoyl]amino]butylcarbamoylamino]ethoxy]ethoxy]acetic acid (LCMS = m / z: 814.56 (M+H+)). The resulting compound then reacted with HOSu in the presence of dicyclohexyl carbodiimide (DCC) to generate a protected succinimide intermediate, which was deprotected with trifluoroacetic acid to generate the title compound (COSu portion). 4. Preparation of 18-[[[(1S)-1-carboxy-4-[[2-[2-[2-[2-(2,5dioxopyrirolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethylamino]-1,1-dimethyl-2-oxo-ethyl]amino]-4oxo-butyl]amino]-18-oxo-octadecanoic acid (D-OSu portion)

[086] The fatty acid side chain was prepared using solid-phase synthesis using 2-chlorotrityl chloride resin as schematically represented in Figure 3. 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid was linked to the 2-chlorotrityl chloride resin in the presence of DIPEA to generate 2-[2-(2Fmoc-aminoethoxy)ethoxy]acetic acid-Resin 2-Cl-Trt. The Fmoc protecting group was removed by selective unlocking of the amino group using piperidine followed by coupling with Fmoc-Aib-OH in THF:DMAc using DIPC and HOBt which generated 2-[2-[(2-Fmoc-amino-2-methyl-propanoyl)amino]ethoxy]ethoxy]acetic acid-Resin 2Cl-Trt. The Fmoc group was removed by selective unlocking using piperidine, and the free amino group was coupled to Fmoc-Glu-OtBu using HOBt and DIPC to generate 2-[2-[[[2-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]-2-methylpropanoyl]amino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt.The Fmoc group of the resulting compound was selectively unblocked using piperidine, and the free amino group was then coupled to mono-tert-butyl octadecanedioic acid ester to obtain... Petition 870260047674, dated 05 / 19 / 2026, p. 47 / 109 31 / 50 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]5-oxo-pentanoyl]amino]-2-methylpropanoyl]-amino]ethoxy]ethoxy]acetic acid-2-ClTrt Resin. The intermediate was then cleaved from 2-ClTrt Resin using trifluoroethanol:DCM (1:1) to obtain 2-[2-[2-[[2-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxooctadecanoyl)amino]-5-oxo-pentanoyl]amino]-2-methylpropanoyl]amino]ethoxy]ethoxy]acetic acid (LCMS = m / z: 786.39 (M+H+)). The resulting compound then reacted with HOSu in the presence of DCC to generate a protected succinimide intermediate, which was deprotected with trifluoroacetic acid to generate the title compound (D-OSu portion). 5. Preparation of 18-[[[(1S)-1-carboxy-4-[3-[2-[2-[2-(2,5dioxopyrrolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethylcarbamoylamino]propylamino]-4-oxobutyl]amino]-18-oxo-octadecanoic acid (E-OSu portion)

[087] The fatty acid side chain was prepared using solid-phase synthesis using 2-chlorotrityl chloride resin as schematically represented in Figure 4. 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid was linked to 2-chlorotrityl chloride resin in the presence of DIPEA to generate 2-[2-(2Fmoc-aminoethoxy)ethoxy]acetic acid-2-Cl-Trt resin. The Fmoc protecting group was removed by selective unlocking of the amino group using piperidine, and the free amino group was then activated using p-nitrophenylchloroformate in THF and DIPEA followed by reaction with 1,3-diaminopropane in THF: DMac in the presence of DIPEA using HOBt to form NH2-(CH2)3-NH-C(O)-{(2-(2-amino-ethoxy)ethoxy}-acetic acid-Resin 2-Cl-Trt. The free amino group was then coupled to Fmoc-GluOtBu using HOBt and DIPC, which generated 2-[2-[2-[3-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxo-pentanoyl]amino]propylcarbamoamino]ethoxy]ethoxy]acetic acid-Resin 2-ClTrt.The resulting 2-[2-[2-[3-[[(4S)-4-Fmoc-amino-5-tert-butoxy-5-oxopentanoyl]amino]propylcarbamoylamino]ethoxy]-ethoxy]acetic acid-Resin 2-Cl-Trt was selectively unblocked using piperidine and then coupled to mono-tert-butyl octadecanedioic acid ester to generate 2-[2-Petition 870260047674, dated 05 / 19 / 2026, p. 48 / 109. 32 / 50 [2-[3-[[(4-S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxopentanoyl]amino]-propylcarbamoylamino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt. The intermediate was then cleaved from Resin 2-Cl-Trt using trifluoroethanol:DCM (1:1) to obtain 2-[2-[2-[3-[[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxooctadecanoyl)amino]-5-oxo-pentanoyl]amino]propylcarbamoylamino]ethoxy]ethoxy]acetic acid (LCMS = m / z: 801.41 (M+H+)). The resulting compound then reacted with HOSu in the presence of dicyclohexyl carbodiimide (DCC) to generate a protected succinimide intermediate, which was deprotected with trifluoroacetic acid to generate the title compound (EOSu portion). 6. Preparation of 18-[[[(1S)-1-carboxy-4-[4-[2-[2-[2-(2,5dioxopyrrolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethylcarbamoylamino]-1-piperidyl]-4-oxobutyl]amino]-18-oxo-octadecanoic acid (F-OSu portion)

[088] The fatty acid side chain was prepared using solid-phase synthesis using 2-chlorotritile chloride resin as schematically represented in Figure 5. 2-[2-(2-Fmoc-aminoethoxy)ethoxy]acetic acid was linked to 2-chlorotritile chloride resin in the presence of DIPEA to generate 2-[2-(2-Fmocaminoethoxy)ethoxy]acetic-Resin 2-Cl-Trt. The Fmoc protecting group was removed by selective unlocking of the amino group using piperidine, and the free amino group was then activated using p-nitrophenylchloroformate in THF and DIPEA, followed by reaction with 4-amino-Boc-piperidine in THF:DMAc in the presence of DIPEA using HOBt, which generated (2-[2-[2-(4-Boc-piperidylcarbamoylamino)ethoxy]ethoxy]acetic acid.The compound resulting from cleavage using trifluoroacetic acid produced 2-[2-[2-(4-piperidylcarbamoylamino)ethoxy]ethoxy]acetic acid which, in further reaction with Fmoc-OSu in the presence of triethylamine (TEA), generated 2-[2-[2-(4-Fmoc-piperidylcarbamoylamino)ethoxy]ethoxy]acetic acid. The obtained compound was then ligated to 2-chlorotrityl chloride resin in the presence of DIPEA to produce 2-[2-[2-(4-Fmoc-piperidylcarbamoylamino)ethoxy]ethoxy]acetic acid-Resin 2Petition 870260047674, dated 05 / 19 / 2026, page 49 / 109. 33 / 50 Cl-Trt. The Fmoc group was removed by selective blocking using piperidine and the free amino group was then coupled to Fmoc-Glu-OtBu using HOBt and DIPC, which generated 2-[2-[2-[[1-[(4S)-4-amino-5-tert-butoxy-5-oxo-pentanoyl]-4-piperidyl]carbamoylamino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt. The resulting compound was selectively unblocked using piperidine and then coupled to monotert-butyl ester of octadecanedioic acid to generate 2-[2-[2-[[1-[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxo-pentanoyl]-4-piperidyl] carbamoylamino]ethoxy]ethoxy]acetic acid-Resin 2-Cl-Trt. The intermediate was then cleaved from 2-Cl-Trt resin using trifluoroethanol:DCM (1:1) to obtain 2-[2[2-[[1-[(4S)-5-tert-butoxy-4-[(18-tert-butoxy-18-oxo-octadecanoyl)amino]-5-oxopentanoyl]-4-piperidyl]carbamoylamino]ethoxy]ethoxy]acetic acid (LCMS= m / z: 827.40 (M+H+)).The resulting compound then reacted with HOSu in the presence of DCC to generate a protected succinimide intermediate, which was deprotected using trifluoroacetic acid to generate the title compound, F-OSu moiety. Example 2: Synthesis of Compound 1:

[089] The activated fatty acid side chain, Portion A-OSu, was prepared by solid-phase synthesis using 2-chlorotrityl chloride resin as schematically represented in Figure 1A. Part A. Synthesis of the linear peptide of origin Aib8, Arg34, Leu38GLP-1(738)

[090] The parent peptide was synthesized by a solid-phase method. The initial resin used for synthesis was Wang resin. Leucine protected by Fmoc was used for coupling with Wang resin. The coupling was performed using diisopropylcarbodiimide, N-hydroxybenzotriazole (DIC-HOBt) as a coupling reagent in the presence of 4-dimethylaminopyridine (DMAP), which generated Fmoc-Leu-Wang resin. Selective unlocking of the amino group of Fmoc-LeuWang resin using piperidine followed by coupling with Fmoc-Gly-OH using HOBt and DIPC generated Fmoc-Gly-Leu-Wang resin. This completes one cycle. Acetic anhydride Petition 870260047674, dated 05 / 19 / 2026, pp. 50 / 109 34 / 50 and diisopropylethylamine / pyridine were used to terminate the uncoupled amino groups in each amino acid coupling.

[091] The 2 steps above, i.e., selective unlocking of the Fmoc protection of the resin-bound amino acid and coupling of the next amino acid residue in sequence with an Fmoc-protected amino group, were repeated for 30 remaining amino acid residues. Selective unlocking, i.e., deprotection of the Fmoc group, was performed using piperidine, and coupling to the next Fmoc-protected amino acid was performed using HOBt / DIPC. The side chain of amino acids protected by Fmoc was orthogonally protected, for example, the hydroxyl group of Serine, Tyrosine or Threonine was protected with the tert-butyl group (-tBu), the amino and guanid groups of Lysine and Arginine were protected with the tert-butyloxycarbonyl group (Boc) and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (-Pbf) respectively, the imidazole of histidine was protected with trityl (-Trt) and carboxylic acid groups of aspartic acid or glutamic acid were protected with the -tBu group.The two steps mentioned above, that is, selective unlocking and then coupling with the next amino acid protected by Fmoc, were performed to obtain FmocHis(Trt)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-ValSer(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Gly-Gln-Ala-Ala-Lys(Boc)-Glu(OtBu)Phe-Ile-Ala-Trp-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-Leu-resin.

[092] Unblocking of Fmoc-His(Trt)-Aib-Glu(OtBu)-Gly-Thr(tBu)-PheThr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-GlyGln-Ala-Ala-Lys(Boc)-Glu(OtBu)-Phe-Ile-Ala-Trp-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)Gly-Leu-Resin using piperidine followed by cleavage and deprotection using trifluoroacetic acid with ethane-1,2-dithiol resulted in H-His-Aib-Glu-Gly-Thr-PheThr-Ser-Asp-Val-Ser- Crude Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-TrpLeu-Val-Arg-Gly-Arg-Gly-Leu-OH (peptide Aib8, Arg34, Leu38GLP-1 (7-38)) that was purified by HPLC. Part B: Petition 870260047674, dated 05 / 19 / 2026, page 51 / 109 35 / 50

[093] Activated fatty acid chain graft, A-OSu portion on HHis-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-AlaLys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-Leu-OH purified (Linear Peptide) obtained in Part A, in acetonitrile at about pH 10 resulted in the crude titer peptide which was purified by preparative HPLC. The characterization of the compounds is provided in Table 3. Example 3: Preparation of Compounds 2, 3, 5, 9, 10 and 12

[094] The linear peptides of compounds 2, 3, 5, 9, 10 and 12 were prepared by a solid phase method, according to the analogous process provided for Example 1, Part A. Grafting of the activated fatty acid chain, Portion A-OSu following the process of Example 1, Part B onto the respective linear peptides generated compounds 2, 3, 5, 9, 10 and 12. Example 4: Preparation of Compounds 4 and 11:

[095] The linear peptides of Compound 4 and 11 were prepared by a solid-phase method, following the analogous process given for Example 2, Part A, except that here, the Fmoc-protected D-Leucine was first coupled to Wang resin and then other amino acids were sequentially coupled. Grafting the activated fatty acid chain, A-OSu Portion, onto the respective linear peptide, following the process of Example 2, Part B, yielded Compound 4 and 11. Example 5: Preparation of Compound 8

[096] The linear peptide was prepared by a solid-phase method, following the analogous process given for Example 2, Part A, except that here, the Fmoc-protected isoleucine was first coupled to Wang resin and then other amino acids were sequentially coupled. Grafting the activated fatty acid chain, Portion A-OSu, onto the linear peptide, following the process of Example 2, Part B, yielded Compound 8. Example 6: Preparation of Compound 6 Petition 870260047674, dated 05 / 19 / 2026, page 52 / 109 36 / 50

[097] The linear peptide was prepared by a solid-phase method, following the analogous process given for Example 2, Part A. Grafting the activated fatty acid chain, Portion B-OSu, onto the linear peptide following the analogous process of Example 2, Part B, yielded Compound 6. Example 7: Preparation of Compound 7

[098] The grafting of the activated fatty acid chain, Portion B-OSu onto the linear peptide of Example 2, Part A, following the analogous process of Example 2, Part B, generated Compound 7. Example 8: Preparation of Compound 13

[099] The grafting of the activated fatty acid chain, C-OSu Portion onto the linear peptide of Example 1, Part A, following the analogous process of Example 1, Part B, generated Compound 13. Example 9: Preparation of Compound 14

[0100] The linear peptide was prepared by a solid-phase method, following the analogous process given for Example 2, Part A. Grafting the activated fatty acid chain, C-OSu Portion, onto the linear peptide following the analogous process of Example 2, Part B, yielded Compound 14. Example 10: Preparation of Compound 15

[0101] The linear peptide was prepared by a solid-phase method, following the analogous process given for Example 2, Part A, starting with Fmoc-protected isoleucine first coupled to Wang resin, and then other amino acids were sequentially coupled. Grafting the activated fatty acid chain, C-OSu moiety, onto the linear peptide following the analogous process of Example 2, Part B, yielded Compound 15. Example 11: Preparation of Compound 16

[0102] The grafting of the activated fatty acid chain, D-OSu Portion onto the linear peptide of Example 2, Part A, following the analogous process of Example 2, Part B, generated Compound 16. Petition 870260047674, dated 05 / 19 / 2026, page 53 / 109 37 / 50 Example 12: Preparation of Compound 17

[0103] The grafting of the activated fatty acid chain, E-OSu Portion onto the linear peptide of Example 2, Part A, following the analogous process of Example 2, Part B, generated Compound 17. Example 13: Preparation of Compound 18

[0104] The grafting of the activated fatty acid chain, F-OSu Portion onto the linear peptide of Example 2, Part A, following the analogous process of Example 2, Part B, generated Compound 18.

[0105] The characterization data of the synthesized compounds in this disclosure are provided below in Table 3. Table 3: Characterization data of representative compounds from this disclosure. Comp. # LCMS Data HPLC Purity 1 m / z = 1057.52 (MH44+), Calculated Mass = 4226.05 98.32% (Method B2), RT=24.85 min. 2 m / z = 1061.74 (MH44+), Calculated Mass = 4242.93 99.02% (Method B1), RT=18.53 min. 3 m / z = 1087.65 (M-4H)'4, Calculated Mass = 4354.63 98.12% (Method B1), RT=18.48 min. 4 m / z = 1055.68 (M-4H)'4, Calculated Mass = 4226.75 98.97% (Method B1), RT=18.32 min. 5 m / z = 1057.88 (MH44+), Calculated Mass = 4227.49 96.75% (Method B1), RT=17.09 min. 6 m / z = 967.26 (MH44+), Calculated Mass: 3865.01 98.68% (Method B3), RT=44.04 min. 7 m / z= 968.53 (M-4H)'4, Calculated Mass = 3878.15 97.39% (Method B3), RT=27.79 min. 8 m / z = 1057.72 (MH44+), Calculated Mass = 4226.85 95.70% (Method B1), RT=16.62 min. 9 m / z = 1061.67 (MH44+), Calculated Mass = 4242.65 95.15% (Method B1), RT=16.48 min. 10 m / z = 1058.18 (MH44+), Calculated Mass = 4228.69 93.66% (Method B1), RT=16.13 min.11 m / z = 1056.95 (MH44+), Calculated Mass: 4223.77 95.70% (Method B2), RT=24.46 min 12 m / z = 1405.12 (MH33+), Calculated Mass: 4212.34 97.51% (Method B1), RT=19.06 min. 13 m / z = 1049.59 (MH4 4+), Mass 96.01% (Method B2),. Petition 870260047674, 19 / 05 / 2026, pág. 54 / 109 38 / 50 Calculated = 4194.33 RT=25.16min. 14 m / z = 1050.13 (MH44+), Calculated Mass = 4196.49 92.06% (Method B2), RT=24.55 min. 15 m / z = 1049.61 (MH44+), Calculated Mass = 4194.41 94.41% (Method B2), RT=24.82 min. 16 m / z = 1042.34 (MH44+), Calculated Mass = 4165.32 94.56% (Method B2), RT=25.26 min. 17 m / z = 1046.18 (MH44+), Calculated Mass = 4180.72 94.33% (Method B2), RT=25.17 min. 18 m / z = 1052.77 (MH4 4+), Calculated Mass = 4207.08 93.12% (Method B2), RT=24.92 min. Example 14: Oral glycose tolerance test (OGTT) in rats; Single Injection; 1 mg / kg

[0106] The animals were divided into three groups – a normal control group, a test group, and a third semaglutide group, with 4 animals in each group. The animals were fasted for 12 hours before the start of the OGTT. For the animals in the test group, Compound 1 was injected subcutaneously at a dose of 1 mg / kg. For the semaglutide group, a dose of 1 mg / kg was injected subcutaneously. After 22 hours, 166 hours, and 334 hours of subcutaneous injection of test drug or semaglutide, blood glucose was measured with a blood glucose meter (measurements at time 0). All animals then received 2 g / kg of glucose solution orally. Blood glucose was measured at 20, 40, 60, 90, and 120 minutes after the glucose challenge. Body weight and food intake were recorded. Blood glucose data were analyzed using two-way ANOVA followed by Bonferroni post-hoc tests using PRISM (Graph Pad version 5.03).Data on blood glucose AUC0-120 min were analyzed using a t-test.

[0107] The polypeptides in this disclosure showed a significant glucose-lowering effect compared to the control group when studied in the Oral Glucose Tolerance Test (OGTT) in rats. For example, Figure 6 shows the change in blood glucose level from time 0 to 120 min. Petition 870260047674, dated 05 / 19 / 2026, page 55 / 109 39 / 50 after 22 hours and 46 hours in the test group administered Compound 1 and in the treatment group with semaglutide. 22 hours after the single dose, Compound 1 showed a statistically significant reduction in blood glucose level with p<0.001 vs normal control in ANOVA followed by Bonferroni post-tests. The glucose-lowering effect of Compound 1 was superior to the glucose-lowering effect observed with semaglutide (see Figure 6A). The superiority of the glucose-lowering effect of Compound 1 was observed even after 46 hours of subcutaneous administration (Figure 6B). Furthermore, Compound 1 and semaglutide showed a statistically significant reduction in food intake compared to the control when observed on day 2 as well as on day 4 (see Tables 4 and 5). The reduced food intake shown by Compound 1 on day 4 was greater than semaglutide (see Table 5).In terms of body weight reduction, only the test compound showed a significant reduction in body weight on day 4. Table 4: Effect of treatment on food intake and body weight on Day 2____________________________________________________________ Food intake (g) (Day 0 to Day 2) Body weight (g) (Day 2) Average SD Average SD % Change vs Reference Normal Control 33.0 4.7 480.6 15.6 8.89 Compound 1 2.63*** 2.5 365.6 21.0 -9.33 Semaglutide 5.03*** 3.4 428.1 42.3 -7.65 *p<0.05, **p<0.01, ***p<0.001 vs Normal Control; One-way ANOVA followed by Bonferroni post-hoc tests Table 5: Effect of treatment on food intake and body weight on Day 4 Petition 870260047674, dated 05 / 19 / 2026, page 56 / 109 40 / 50 Food intake (g) (Day 0 to Day 4) Body weight (g) (Day 4) Average SD Average SD % Change vs Reference Normal Control 90.5 5.6 491.3 16.9 2.1 Compound 1 43.25*** 2.8 436.2* 21.1 -7.5 Semaglutide 55.73*** 4.1 427.2 42.3 -5.3 *p<0.05, **p<0.01, ***p<0.001 vs Normal Control; One-way ANOVA followed by Bonferroni post-tests #p<0.05, ##p<0.01, ###p<0.001 vs Semaglutide; One-way ANOVA followed by Bonferroni post-tests

[0108] Surprisingly, compounds with X33 such as Leu and Ile were found to show a significant reduction in blood glucose in the determined studies, while compounds with amino acids other than Leu and Ile had significantly less effect on reducing blood glucose. The polypeptide of the present disclosure showed a significant reduction in blood glucose when compared to the control group. Compounds with amino acids other than Leu or Ile at the X33 positions were also tested. For example, Leu at the 32nd position in Compound 1 (SEQ ID NO:05) was replaced by Lys and Ser to obtain compounds Std-1 and Std-2, respectively. Std-1 and Std-2 showed only about 35% and 15% reduction in blood glucose AUC0-120 min (Table 6). Table 6: Percentage reduction in blood glucose AUC 0-120 min in the OGTT test at a dose of 1 mg / kg after 24 hours. Petition 870260047674, dated 05 / 19 / 2026, page 57 / 109 41 / 50 Comp. # % Glucose Reduction Semaglutide comp / std Comp. # % Glucose Reduction Liraglutide Comp / std Std-1 35.1 0.71 6 75.8 1.83 Std-2 14.8 0.30 7 71.9 1.73 Semaglutide 49.3 Liraglutide 41.5

[0109] Similarly, compound 6, which differs from liraglutide by having an additional Leu in the 32nd position, and compound 7, which differs from liraglutide by having the 2nd amino acid Ala replaced by Aib and having Leu as an additional 32nd amino acid, showed a blood glucose-lowering effect over 24 hours that was significantly greater than liraglutide (Table 6).

[0110] Once it was established that Compound 1 was significantly better in terms of glucose reduction, food intake, and body weight reduction, experiments were conducted to determine the duration of action of the compound of the present invention. The effect of the representative compounds of the present invention (Compound 1, 13, and 16) after 166 hours (7 days) and 334 hours (14 days) was studied and compared with that of semaglutide. The compounds were tested according to the method provided below:

[0111] The animals were divided into three groups – a normal control group, a test group, and a third semaglutide group, with 4 animals in each group. The animals were fasted for 12 hours before the start of the OGTT. For the test group animals, Compound 1, Compound 13, and Compound 16 were injected subcutaneously at a dose of 1 mg / kg. For the semaglutide group, a dose of 1 mg / kg was injected subcutaneously. After 22 hours, 166 hours, and 334 hours of subcutaneous injection of the test compound or semaglutide, blood glucose was measured with a blood glucose meter (measurements at time 0). All animals then received 2 g / kg of glucose solution orally. Blood glucose was measured at 20, 40, 60, 90, and 120 minutes after the glucose challenge. Body weight and food intake were recorded. Blood glucose data were analyzed using two-way ANOVA followed by... Petition 870260047674, dated 05 / 19 / 2026, pp. 58 / 109 42 / 50 Bonferroni post-tests using PRISM (Graph Pad version 5.03). Blood glucose AUCo120 min data were analyzed using the t-test.

[0112] Table 7 provides the reduction in blood glucose AUC for the representative compounds of the present invention (Compound 1, 13 and 16) compared with the control group after 1 day, 7 days and 14 days of administration. Table 7: Percentage reduction in blood glucose AUC 0-120 min in OGTT treatment at a dose of 1 mg / kg. Compound # Time Blood glucose AUC (mg / dL*min) Change in AUC (mg / dL*min) Mean Semaglutide Exp. 1 22 hours 5458.0 -63.4 168 hours 12785.0 -25.5 336 hours 16223.0 -2.4 Comp. 1 Exp. 1 22 hours 3173.0 -78.7 168 hours 5941.0 -65.4 336 hours 11920.0 -28.3 Comp. 13 Exp. 1 22 hours 2795.0 -81.2 168 hours 6950.0 -59.5 336 hours 11368.0 -31.6 Semaglutide Exp. 2 22 hours 4258 -50 168 hours 7410 -26.6 336 hours 8023.0 -5.5 Comp. 16 Exp. 2 22 hours 1646 -80.7 168 hours 4283 -57.6 336 hours 8295.0 -2.3

[0113] Compounds 1 and 13 were studied and compared with semaglutide in an experiment (Exp. 1), and Compound 16 was studied and compared with semaglutide in a separate experiment (Exp. 2). After 168 hours of injection, Compounds 1, 13, and 16 of the present invention showed approximately Petition 870260047674, dated 05 / 19 / 2026, pp. 59 / 109 43 / 50 A 60% reduction in blood glucose AUC compared to baseline blood glucose levels. On the other hand, semaglutide showed only about a 25% reduction in blood glucose levels relative to baseline blood glucose levels.

[0114] Similar observations were made regarding the amount of food consumed and changes in body weight. As can be seen in Table 8 below, animals administered with the representative compounds (Compound 1, 13, and 16) consumed significantly less food when compared to animals administered with semaglutide. Compound 16 showed a substantial reduction in body weight, demonstrating potential usefulness for the treatment of obesity. Table 8: Effect on food consumption and body weight in the OGTT test at a dose of 1 mg / kg Compound # Time Food Consumption (g) Change in Body Weight (%) Average Average Semaglutide Exp. 1 48 h 17.5 -6.5 154 h 86.3 4.5 324 h 107.9 11.8 Comp. 1 Exp. 1 48 h 8.3 -9.8 154 h 69.6 5.2 324 h 99.4 9.3 Comp. 13 Exp. 1 48 h 8.4 -10.2 154 h 62.3 4.5 324 h 82.44 8.2 Semaglutide Exp. 2 48 h 19.3 -8.7 154 h 50.4 0.2 324 h 96.8 3.8 Comp. 16 Exp. 2 48 h 5.9 -10.7 154 h 44.1.0 -7.0 Petition 870260047674, dated 05 / 19 / 2026, pp. 60 / 109 44 / 50 324 h 104.3 -4.3 Example 15: Reduction of HbA1c in db / db type 2 diabetic mice after chronic treatment.

[0115] This study was conducted in a diabetic mouse model. The animals were divided into three treatment groups – a diabetic control group, a test group, and a semaglutide treatment group. Compound 1 of this disclosure was injected subcutaneously at a dose of 0.3 mg / kg once daily for 3 days (qd*3) followed by a dose of 0.1 mg / kg on alternate days for 7 doses (q2d*7) followed by a dose of 0.1 mg / kg once every four days for two dosing cycles (q4d*2). The same dosing regimen was administered to the semaglutide treatment group. Blood glucose levels and body weight were measured daily. %HbA1c was measured on Day 0, Day 7, Day 14, and Day 27 by column chromatography. Cumulative food intake was calculated on day 27. %HbA1c data were analyzed by two-way ANOVA followed by Bonferroni post-hoc tests using PRISM (Graph Pad version 5.03).

[0116] Animals in the test group administered with Compound 1 showed a statistically significant reduction in blood glucose levels compared to the diabetic control group (see Figure 7), and the effect was superior to the semaglutide treatment group in the last phase of the study. Animals in the test group administered with Compound 1 showed a significant reduction in food intake, as can be seen in the results provided in Figure 8. Figure 8 provides cumulative food intake from day 0 to day 27 for control and db / db mice treated with the test compound. Both the test compound and semaglutide showed a statistically significant reduction in food intake compared to the diabetic control group. In addition, the test compound showed an intake Petition 870260047674, dated 05 / 19 / 2026, pp. 61 / 109 45 / 50 of food significantly less, compared to semaglutide. In the same study, Compound 1 also showed a significant reduction in body weight when compared to the diabetic control group. Figure 9 provides the result of the % change in body weight for the control and test groups from day 0 to day 27. Test compound 1 showed a significant reduction of -16% compared to -8% as observed in the semaglutide treatment group (see Figure 9).

[0117] In diabetes mellitus, higher HbA1c levels, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, nephropathy, neuropathy, and retinopathy. In a 27-day study, Compound 1 showed a statistically significant reduction in HbA1c levels in db / db type 2 diabetic mice after chronic treatment. Table 9 below and Figure 10 provide the HbA1c levels on days 0 and 27 in the Diabetic control group and the group after chronic treatment with Compound 1. The effect was statistically significant even when compared to semaglutide. Table 9: Effect of treatment on % of HbA1c levels in db / db mice Time Point (days) % of HbA1c Diabetic Control (DC) Composite 1 Semaglutide Mean SD n Mean SD n % Change vs DC Mean SD n % Change vs DC 0 4.70 0.52 6 4.87 0.59 6 5.05 0.35 5 27 7.30 1.17 6 3.73***## 0.86 6 -3.57 5.03*** 0.69 5 -2.26 *p<0.05, **p<0.01, ***p<0.001 vs Diabetic Control; Two-way ANOVA followed by Bonferroni post-test #p<0.05, ##p<0.01, ###p<0.001 vs Semaglutide; One-way ANOVA followed by Bonferroni post-tests Petition 870260047674, dated 05 / 19 / 2026, p. 62 / 109 46 / 50

[0118] In a separate study, test compounds 1, 13, and 16 were studied and compared with semaglutide for their effect on HbA1c and insulin levels and cumulative food intake, change in body weight, and blood glucose AUC. The study was conducted similarly as above in a diabetic mouse model. The animals were divided into three treatment groups – a diabetic control group, a test group, and a semaglutide treatment group. The representative compounds of this disclosure, Compound 1, Compound 13, and Compound 16, were injected subcutaneously at doses of 3.04 or 6.078 nM (on alternate days until day 28 (q2d*15)). The same dosing regimen was administered to the semaglutide treatment group. Blood glucose levels and body weight measurements were taken daily. % HbA1c, insulin was measured on Day 0, Day 14, and Day 29.Cumulative food intake and change in body weight were calculated on days 14 and 29. %HbA1c and insulin data were analyzed by two-way ANOVA followed by Bonferroni post-hoc tests using PRISM (Graph Pad version 5.03). While blood glucose AUC, change in body weight, and cumulative food intake data were analyzed by one-way ANOVA followed by Bonferroni post-hoc tests using PRISM (Graph Pad version 5.03). From day 29 to day 45, animals were kept in the recovery period during which no drug treatment was administered. Blood glucose and body weight were measured during this period. On day 45, changes in body weight, %HbA1c, and insulin were measured.

[0119] The results are provided in Tables 10, 11 and 12 below. Table 10: HbA1C (%): Compound 1 (6.078 nM), Compound 13 (3.04 & 6.078 nM), Compound 16 (3.04 & 6.078 nM); (q2d*15) (n=7) Petition 870260047674, dated 05 / 19 / 2026, pp. 63 / 109 47 / 50 Point to time (days) % HbA1C Diabetic Control 0 (DC) Compound 1, 6.078nM, q2d*15 Compound 13, 3.04nM, q2d*15 Compound 13, 6.078nM, q2d*15 Compound 16, 3.04nM, q2d*15 Compound 16, 6.078nM, q2d*15 Semaglutide, 12.15nM, q2d*15 Average SD Average SD Average SD Average SD Average SD Average SD Average SD Average SD 0 7.7 1.2 7.8 0.8 7.7 1.5 7.8 3 0.76 7.7 4 1.27 7.8 3 0.99 7.6 6 1.1 3 14 8.0 1.0 6.4 ** 0.5 6.6* 0.9 6.0 0 *** 0.53 5.6 7 ***# 0.68 5.6 4 ***# 0.49 7.0 4 1.1 5 29 8.3 1.0 6.2 *** 0.5 6.4 *** 0.8 5.6 4 *** 0.51 5.3 3 ***# 0.39 5.1 6 ***# 0.24 6.4 7 *** 1.0 3 *=p<0.05, **=p<0.01, ***=p<0.001 vs. Diabetic Control, #p<0.05, ##p<0.01, ###p<0.001 vs. Semaglutide; One-way ANOVA followed by Bonferroni post-hoc tests. Table 11: Insulin (ng / mL): Compound 1 (6.078 nM), Compound 13 (3.04 & 6.078 nM), Compound 16 (3.04 & 6.078 nM); (q2d*15) (n=7) Time Point (days) Insulin (ng / mL) Diabetic Control Composite 1, 6.078nM, q2d*15 Composite 13, 3.04nM, q2d*15 Composite 13, 6.078nM, q2d*15 Composite 16, 3.04nM, q2d*15 Composite 16, 6.078nM, q2d*15 Sema, 12.15 nM, q2d*15 Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD 0 17.6 5.5 18.0 5.8 21.7 12.1 26.2 14.0 13.9 6.6 21.8 9.6 18.7 10.3 14 23.0 10. 7 58.1** 31.6 41.8 28.2 61.2** * 23.7 50.8 * 27.7 58.1* * 12.5 37.5 26.5 Petition 870260047674, dated 05 / 19 / 2026, pp. 64 / 109 48 / 50 29 16.9 6.6 54.7** 6.4 54.4 ** 27.0 59.4** * 22.4 53.8 ** 23.5 68.2* ** 27.1 48.1 ** 25.3 *=p<0.05, **=p<0.01, ***=p<0.001 vs Diabetic Control, #p<0.05, ##p<0.01, ###p<0.001 vs Semaglutide; One-way ANOVA followed by Bonferroni post-hoc tests. Table 12: Cumulative food intake, blood glucose AUC (mg / dL*days) and changes in body weight: Compound 1 (6.078 nM), Compound 13 (3.04 & 6.078 nM), Compound 16 (3.04 & 6.078 nM); (q2d*15) Groups (n=7) Intake cumulative food intake Day 0-29 Active intake of tos (g) Blood glucose AUC (Day 0-29) (mg / dL*days) Change in body weight Day 29, % change x Day 0 Mean SD Mean SD % Change vs control Mean SD Diabetic control 99.3 37.16 16948.1 281.48 9.4 6.4 Compound 1, 6.078 nM 79.8 25.09 9194.6*** 450.84 -45.75 -0.3 2.2 Compound 13, 3.04 nM 75.2 18.45 9515.4*** 805.21 -43.86 1.2 3.8 Compound 13, 6.078 nM 70.4 10.85 8451.7***## 612.94 -50.13 -1.1 2.4 Compound 16, 3.04 nM 77.4 23.82 9399.0*** 680.38 -44.54 -1.4 5.4 Compound 16, 6.078 nM 66.7 29.48 8086.1***## 623.80 -52.29 -5.5 3.1 Semaglutide, 12.155 nM 92.0 6.64 9867.9*** 832.73 -41.78 0.7 3.9 *=p<0.05, **=p<0.01, ***=p<0.001 vs Diabetic Control, #p<0.05, ##p<0.01, ###p<0.001 vs Semaglutide; One-way ANOVA followed by Bonferroni post-hoc tests.

[0120] The representative compounds of this disclosure (Compounds 1, 13, and 16) at doses of approximately 3 nM and 6 nM showed significant reductions in HbA1c, blood glucose, food intake, and body weight when compared to the control (Table 12). The reduction was comparable to that shown Petition 870260047674, dated 05 / 19 / 2026, pp. 65 / 109 49 / 50 by semaglutide at approximately 12 nM dose. Furthermore, the effect was seen even after 29 days (Tables 13 and 14), which demonstrates the potential of the compounds of the present invention to develop long-acting drugs that do not require frequent administration and therefore add to patient compliance. Table 13: Recovery study - Blood glucose AUC (mg / dL*days) Groups (n=3) Blood glucose AUC (Day 30-37) (mg / dL*days) % Change vs Control Blood glucose AUC (Day 38-45) (mg / dL*days) % Change vs Control Mean SD Mean SD Diabetic control 3591.7 47.04 3601.7 38.66 Composite 1, 6.078 nM 2787.3* 17.67 -22.39 3335.7 66.11 -7.39 Composite 13, 3.04 nM 2588.7** 411.97 -27.93 3401.0 61.00 -5.57 Composite 13, 6.078 nM 2875.7 436.87 -19.94 3361.0 205.83 -6.68 Compound 16, 3.04 nM 2420.0** 89.71 -32.62 3284.0* 81.66 -8.82 Compound 16, 6.078 nM 2167.7*** 210.19 -39.65 3134.7** 103.39 -12.97 Semaglutide, 12.155 nM 3032.0 182.40 -15.58 3415.7 88.82 -5.16 *p<0.05, **p<0.01, ***p<0.001 vs Diabetic Control and #p<0.05, ##p<0.01, ###p<0.001 vs Semaglutide; One-way ANOVA followed by post-hoc tests. Bonferroni Table 14: Recovery study - %HbA1c and Insulin (ng / mL) Groups (n=3) % HbA1 C Delta HbA1C vs. DC Insulin (ng / mL) % Change Body weight vs Day 45 Mean SD Mean SD Mean SD Diabetic control 8.5 0.4 20.6 12.0 7.8 1.08 Composite 1, 6.078 nM 7.6 0.5 -0.9 30.9 8.9 5.9 3.68 Composite 13, 3.04 nM 7.5 0.4 -1.0 31.2 32.7 6.6 0.86 Composite 13, 6.0788 nM 7.3 0.4 -1.2 34.3 12.4 5.5 2.19 Composite 16, 3.04 nM 7.1* 0.2 -1.4 15.5 8.2 6.1 0.38 Composite 16, 7.2 * 0.5 -1.3 18.4 18.7 5.7 0.36 Petition 870260047674, dated 05 / 19 / 2026, p. 66 / 109 50 / 50 6.078 nM Semaglutide, 12.155 nM 7.8 0.3 -0.7 19.7 4.2 9.5 4.68 *p<0.05, **p<0.01, ***p<0.001 vs Diabetic Control and #p<0.05, ##p<0.01, ###p<0.001 vs Semaglutide; One-way ANOVA followed by Bonferroni post-hoc tests.

[0121] These results demonstrate that the compound of the present invention may find potential use for the treatment of diabetes and obesity. Petition 870260047674, dated 05 / 19 / 2026, pp. 67 / 109

Claims

1 / 13 CLAIMS 1. Polypeptide CHARACTERIZED in that it comprises the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34, wherein X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib; X3 is absent or is Gln; X4 is Glu; X16 is Glu; X24 is Ile; X33 is Leu, -D-Leu, D-Ile or Ile; X34 is absent; and X21 is Lys, wherein the side chain amino group (S amino) of Lys is acylated with a moiety: {—QT—UWYZ, wherein Q and T are absent; U is absent or is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}, where} is the point of attachment to group W; W is absent or is selected from a group consisting of -C(O)CH2-O-(CH2)2-O-(CH2)2-NH-], -C(O)-NH-(CH2)3-4-NH-], -C(O)-C(CH3)2-NH-]; and -C(O)-NH-( N—] \— / , where ] is the point of attachment to group Y; Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is a point of attachment to group Z; Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3, where n is an integer from 14 to 20.

2. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Aib; X3 is absent; Petition 870260047674, dated 05 / 19 / 2026, page 68 / 109 2 / 13 X33 is Leu; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}; W is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-]; and Z is -C(O)-(CH2)n-COOH, where n is the integer 16.

3. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}; W is -C(O)-C(CH3)2-NH-]; and Z is -C(O)-(CH2)n-COOH, wherein n is the integer 16.

4. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}; W is -C(O)-NH-(CH2)4-NH-]; and Z is -C(O)-(CH2)n-COOH, wherein n is the integer 16.

5. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}; ... C -C(O)-NH^^N-] W is \— / ; and Z is -C(O)-(CH2)n-COOH, where n is the integer 16.

6. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Aib; X3 is absent; Petition 870260047674, dated 05 / 19 / 2026, page 69 / 109 3 / 13 X33 is Leu; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}; W is -C(O)-NH-(CH2)3-NH-]; and Z is -C(O)-(CH2)n-COOH, where n is the integer 16.

7. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe); X3 is absent; X33 is Leu; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}; W is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-], -C(O)-NH-(CH2)3-4-NH-], -C(O)C(CH3)2-NH-]; and Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3, wherein n is an integer from 14 to 20.

8. Polypeptide, according to claim 1, CHARACTERIZED in that W is selected from a group consisting of -C(O)-NH-(CH2)3-4-C(O)-NH NH-], -C(O)-C(CH3)2-NH-] and 9. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Ala; X3 is absent; X33 is Leu; W is absent; Z is -C(O)-(CH2)n-CH3, where n is the integer 14.

10. Polypeptide, according to claim 1, CHARACTERIZED in that X2 is Aib; X3 is absent; X33 is Leu; W is absent; Z is -C(O)-(CH2)n-CH3, where n is the integer 14. Petition 870260047674, dated 05 / 19 / 2026, p. 70 / 109 4 / 13 11. Polypeptide CHARACTERIZED by the fact that it comprises the amino acid sequence: HO HN JJH EGTFTSDVSSYLEGQAA—NO EFIAWLVRGRGL (a) FRACTION (SEQ ID NO: 5), H-Ser(OMe)-EGTFTSDVSSYLEGQAA EFIAWLVRGRGL (b) (SEQ ID NO: 6), FRACTION QEGTFTSDVSSYLEGQAA— y A „NH EFIAWLVRGRGL (c) (SEQ ID NO: 7), FRACTION y A-NH HO HO H—N EGTFTSDVSSYLEGQAAN (d) (SEQ ID NO: 8), FRACTION HSEGTFTSDVSSYLEGQAA y A NH EFIAWLVRGRGL (e) (SEQ ID NO: 9), - ,NH FRACTION . a' Petition 870260047674, of 05 / 19 / 2026, p.71 / 109 5 / 13 H O H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A —n E-F-I-A-^V-L-V-R-G-R-G-L (f) (SEQ ID NO: 10), - NH FRAÇÃO , b H O HO H-N U-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A—N E-F-I-A-W-L-V-R-G-R-G-L (g) (SEQ ID NO: 5), - NH FRAÇÃO y b-nh H O HO H-N U-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A—n e-f-i-a-w-l-v-r-g-r-g-i (h) (SEQ ID NO: 11), - ^NH FRAÇÃO A' H O H-(DSer(OMe))-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A—N E-F-I-A-W-L-V-R-G-R-G-L (i) (SEQ ID NO: 12), - .,nh FRAÇÃO ·A H O H-(DSer)-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-N E-F-I-A-W-L-V-R-G-R-G-L (j) (SEQ ID NO: 13), - ^NH FRAÇÃO A' Petição 870260047674, de 19 / 05 / 2026, pág. 72 / 109 6 / 13 H O H O H-frJl- Q-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-N Λ (k) FRAÇÃO ' A' (SEQ ID NO: 14), H O H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A—N U— - E-F-I-A-W-L-V-R-G-R-G-(DLeu) ,NH E-F-I-A-W-L-V-R-G-R-G-L ...^Sh (l) FRACTION A (SEQ ID NO: 10), HOHO HN 1L_ EGTFTSDVSSYLEGQAA—N Λ FRACTION (m) C (SEQ ID NO: 5), HO HSEGTFTSDVSSYLEGQAA —N 11— E - ''^Nl· (n) FRACTION C (SEQ ID NO: 9), HOHO HN^IL- egtftsdvssylegqaan I1- (o) FRACTION · C' (SEQ ID NO: 11), 1 - EFIAWLVRGRGL „NH -FIAWLVRGRGL H - EFIAWLVRGRGI NH Petition 870260047674, dated 19 / 05 / 2026, p. 73 / 109 7 / 13 HOHO HN UEGTFTSDVSSYLEGQAA—N I1— EFIAWLVRGRGL (p) (SEQ ID NO: 5), FRACTION HOH HN JJ—EGTFTSDVSSYLEGQAA—N (q) (SEQ ID NO: 5), FRACTION HOH H-Nk JJ—EGTFTSDVSSYLEGQAA—N (r) (SEQ ID NO: 5), NH O Jl— EFIAWLVRGRGL _.NH EEOE— EFIAWLVRGRGL - NH FRACTION .* O; ; in which portion B has the structure: Petition 870260047674, dated 05 / 19 / 2026, page 74 / 109 8 / 13 in which portion E has the structure: in which portion F has the structure:

12. Polypeptide CHARACTERIZED by the fact that it comprises the amino acid sequence: Petition 870260047674, dated 05 / 19 / 2026, page 74 / 10975 / 109 9 / 13 H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34 (SEQ ID NO: 15), wherein X2 is Ser, Ser(OMe), Aib, Ala, Gly, Vai, Leu, lie, (1-aminocycloalkyl C3-8) carboxylic acid, Trp or Thr; X3 is absent or is Gin; X4 is Gin or Glu; X16 is Glu or Asp; X24 is lie or Vai or Leu; X33 is Leu, lie, Tyr or is absent; X34 is Ser, Lys, Ala or is absent; and X21 is Lys, wherein the side-chain amino group (8 amino) of Lys is acylated with a moiety: {-QTUWYZ wherein Q, T, U and W are absent or selected from the group consisting of -C(O)-M-NH-; wherein M is a C5-10 alk chain interrupted by 1, 2 or 3 oxygen atoms, -C(O)-N(Ri)-alk C2-5-N(Ri)-, -C(O)-C(CH3)2-N(R2); and R3 MI / Π-2 -C(O)—N—Ç N-- M1-2 wherein Ri, R2 or R3 are independently selected from hydrogen or C1-3 alkyl; provided that: i. at least one of Q, T, U and W is always present; and ii.at least one of Q, T, U and W is always selected from the groups -C(O)-N(R1)-alk C2-5 -N(R1)-, -C(O)-C(CH3)2-N(R2)-; and Petition 870260047674, of 19 / 05 / 2026, page 76 / 109 10 / 13 R3 -C(O)-N \1—2 N-11-2 ; Y is absent or is -C(O)-(CH2)m-CH(COOH)NH--, where m is an integer selected from 1 or 2 and -- is a point of connection with the group Z; Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3, where n is an integer from 10 to 20.

13. Compound CHARACTERIZED by the fact that it has the formula: where: n is an integer from 14 to 20; and Ro is CO2H or CH3.

14. Process for preparing a compound having the formula MD: wherein: n is an integer from 14 to 20, CHARACTERIZED in that the process comprises: a) coupling a compound of formula D1: Petition 870260047674, dated 19 / 05 / 2026, page 77 / 109 11 / 13 with amino-protected 2-amino-2-methylpropanoic acid to prepare a compound of formula D2: wherein R2 is a nitrogen protecting group; b) deprotecting the compound of formula D2 and reacting the deprotected compound with glutamic acid, wherein the carboxy in position 1 and the amino nitrogen of glutamic acid are protected, to provide a compound of formula D3: wherein R3 is a lower alkyl and R4 is an amino protecting group; c) remove R3 from the compound of formula D3 and couple the unprotected compound with a mono-alkyl ester of a C16-C22 diacid to prepare a compound of formula D4: wherein Ri is a C1-C4 alkyl; d) react the compound of formula D4 with N-hydroxysuccinimide; and e) remove Ri and R3.

15. Compound CHARACTERIZED by the fact that it has the formula D2: Petition 870260047674, dated 05 / 19 / 2026, page 78 / 109 12 / 13 where R2 is H or a nitrogen protecting group.

16. Compound CHARACTERIZED by the fact that it has the formula D3: where: R3 is H or a lower alkyl group; and R4 is H or a nitrogen protecting group.

17. Compound CHARACTERIZED by the fact that it has the formula: where: R3 is H or lower alkyl; and Ri is H or C1-C4 alkyl.

18. Polypeptide CHARACTERIZED by the fact that it comprises the amino acid sequence: H-X2-X3-X4-GTFTSDVSSYL-X16-GQAA-X21-EF-X24-AW-LV-RGRG-X33-X34, wherein X2 is Ser, Ser(OMe), Aib, Ala, Gly, Val, Leu, Ile, (1-aminocycloalkyl C3-8) carboxylic acid, Trp or Thr; X3 is absent or is Gln; X4 is Gln or Glu; Petition 870260047674, dated 05 / 19 / 2026, page 79 / 109 13 / 13 X16 is Glu or Asp; X24 is Ile or Val or Leu; X33 is Leu, Ile, Tyr or is absent; X34 is Ser, Lys, Ala, amide, or absent; and X21 is Lys, wherein the side-chain amino group (S amino) of Lys is acylated with a moiety: {--QTUWYZ , wherein Q and T are absent; U is -C(O)-CH2-O-(CH2)2-O-(CH2)2-NH-}, wherein} is the point of attachment to group W; W is -C(O)-C(CH3)2-NH-], wherein ] is the point of attachment to group Y; Y is -C(O)-(CH2)2-CH(COOH)NH-- and -- is a point of attachment to group Z; Z is -C(O)-(CH2)n-COOH or -C(O)-(CH2)n-CH3, wherein n is an integer from 10 to 20.

19. Use of a polypeptide, as defined in any one of claims 1, 11, 12 and 18, CHARACTERIZED by the fact that it is for the manufacture of a medicament for the treatment of diabetes in a patient in need thereof.

20. Pharmaceutical composition CHARACTERIZED by the fact that it comprises a polypeptide or a salt thereof, as defined in any of claims 1, 11, 12 and 18, together with one or more pharmaceutically acceptable excipients. Petition 870260047674, dated 19 / 05 / 2026, pp. 80 / 109

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