WO2010016936A1 - Compositions pharmaceutiques d'analogues de polypeptide insulinotrope glucose-dépendant - Google Patents

Compositions pharmaceutiques d'analogues de polypeptide insulinotrope glucose-dépendant Download PDF

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Publication number
WO2010016936A1
WO2010016936A1 PCT/US2009/004545 US2009004545W WO2010016936A1 WO 2010016936 A1 WO2010016936 A1 WO 2010016936A1 US 2009004545 W US2009004545 W US 2009004545W WO 2010016936 A1 WO2010016936 A1 WO 2010016936A1
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seq
hgip
aib
cys
nle
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PCT/US2009/004545
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English (en)
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Zheng Xin Dong
Jundong Zhang
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Ipsen Pharma S.A.S.
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Publication of WO2010016936A1 publication Critical patent/WO2010016936A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins

Definitions

  • the present invention relates to improvements in compositions containing an analogue of glucose-dependent insulinotropic polypeptide or pharmaceutical salts thereof, and the use of such compositions for treatment of GIP -receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity.
  • the present invention relates to a pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid, comprising the native GIP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (which are collectively referred to as "GIP peptide” or “GIP compound”), and a divalent metal or divalent metal salt component such as ZnCl 2 or ZnAc 2 , in which the clear aqueous solution of the GIP peptide precipitates in vivo at physiological pH to form an in situ deposit that is slowly dissolved and released into the body fluid and bloodstream.
  • a pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid comprising the native GIP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (which are collectively referred to as "GIP peptide” or “GIP compound”), and a divalent metal or divalent metal salt component such as ZnCl 2 or Zn
  • GIP Glucose-dependent insulinotropic polypeptide
  • gastric inhibitory polypeptide is a 42 -residue peptide secreted by enteroendorine K-cells of the small intestine into the bloodstream in response to oral nutrient ingestion. GIP inhibits the secretion of gastric acid, and it has been shown to be a potent stimulant for the secretion of insulin from pancreatic beta cells after oral glucose ingestion (the "incretin effect") (Creutzfeldt, W., et al, 1979, Diabetologia, 16:75-85).
  • GIP and glucagon-like peptide 1 appear to fulfill the requirements to be considered physiological stimulants of postprandial insulin release (Nauck, et al., 1989, J. CHn. Endorinol. Metab., 69:654- 662).
  • GIP GIP-associated diabetes
  • a disease selected from the group consisting of type 1 diabetes, type 2 diabetes (Visboll, T., 2004, Dan. Med. Bull., 51 :364-70), insulin resistance (WO 2005/082928), obesity (Green, B. D., et al, 2004, Current Pharmaceutical Design, 10:3651-3662), metabolic disorder (Gault, V. A., et al, 2003, Biochem. Biophys. Res.
  • GIP pancreatic beta cells
  • GIP In addition to effects on the pancreas to enhance insulin secretion, GIP also has effects on insulin target tissues directly to lower plasma glucose: enhancement of glucose uptake in adipose (Eckel, et al, 1979, Diabetes, 28: 1141-1142) and muscle (O'Harte, et al, 1998, J.
  • a GIP receptor antagonist in accordance with the present invention inhibits, blocks or reduces glucose absorption from the intestine of an animal.
  • therapeutic compositions containing GIP antagonists may be used in patients with non- insulin dependent diabetes mellitus to improve tolerance to oral glucose in mammals, such as humans, to prevent, inhibit or reduce obesity by inhibiting, blocking or reducing glucose absorption from the intestine of the mammal.
  • PCT publication WO 00/58360 discloses peptidyl analogues of GIP which stimulate the release of insulin.
  • this application discloses specific peptidyl analogues comprising at least 15 amino acid residues from the N-terminal end of GIP(l-42) (SEQ ID NO:1), e.g., an analogue of GIP containing exactly one amino acid substitution or modification at positions 1, 2 and 3, such as (Pro 3 )GIP(l-42) (SEQ ID NO:9).
  • PCT publication WO 98/24464 discloses an antagonist of GIP consisting essentially of a 24- amino acid polypeptide corresponding to positions 7-30 of the sequence of GIP, a method of treating non-insulin dependent diabetes mellitus and a method of improving glucose tolerance in a non-insulin dependent diabetes mellitus patient.
  • PCT publication WO 03/082898 discloses C-terminal truncated fragments and N-terminal modified analogues of GIP, as well as various GIP analogues with a reduced peptide bond or alterations of the amino acids close to the DPPIV-specific cleavage site.
  • This application further discloses analogues with different linkers between potential receptor binding sites of GIP. The compounds of this application are alleged to be useful in treating GIP-receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity.
  • improved sustained release GIP formulations that provide sustained release profile upon subcutaneous injection.
  • improved sustained release GIP formulations comprise novel analogues of GIP as illustrated herein which are stable in formulation and have long plasma half-life in vivo resulting from decreased susceptibility to proteolysis and decreased clearance while maintaining binding affinity to a GIP receptor to elicit respective agonistic or antagonistic effects.
  • tighter control of plasma glucose levels may prevent long-term diabetic complications, thereby providing an improved quality of life for patients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the native GIP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof.
  • novel analogues of GIP are particularly preferred.
  • Example 1 (A5c 11> 41 )hGIP(l-42)-OH (SEQ ID NO: 15);
  • Example 5 (Aib 13 , Asp 43 )hGIP(l-43)-NH2 (SEQ ID NO: 19);
  • Example 6 (Aib 13 , NIe 14 , A5c 40 )hGIP(l-42)-OH (SEQ ID NO:20);
  • Example 7 (Aib 13 , A5c 40 )hGIP(l-42)-OH (SEQ ID NO:21);
  • Example 8 (A5c", Ala 43 )hGIP(l-43)-OH (SEQ ID NO:22);
  • Example 10 (A5c ⁇ , Thr 43 )hGIP(l-43)-OH (SEQ ID NO:24);
  • Example 11 (AOc 11 ' 14 4l )hGIP(l-42)-OH (SEQ ID NO:25);
  • Example 12 (Aib 13 , Trp 43 )hGIP(l-43)-OH (SEQ ID NO:26);
  • Example 13 (A5c n , Ado 43 )hGIP(l-43)-OH (SEQ ID NO:27);
  • Example 14 (A6c"' l4 ' 40 )hGIP(l-42)-OH (SEQ ID NO:28);
  • Example 15 [A6c 7 , Cys(Psu) 42 ]hGIP(l-42)-OH (SEQ ID NO:29);
  • Example 16 (A6c 7 ' 4I )hGIP(l-42)-OH (SEQ ID NO:30);
  • Example 17 (A6c 7 ' 41 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:31);
  • Example 18 [A6c 7 , Om 35 (N-C(O)-(CH 2 ) 12 -CH 3 )]hGIP(l-42)-OH (SEQ ID NO:32);
  • Example 19 [A6c 7 , Orn 31 (N-C(O)-(CH 2 ) 12 -CH 3 )]hGIP(l-42)-OH (SEQ ID NO:33);
  • Example 20 (A5c n ' 14 , His 43 )hGD?(l-43)-OH (SEQ ID NO:34);
  • Example 21 (A5c n , NIe 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:35);
  • Example 22 [A5c ⁇ , Orn 32 (N-C(O)-(CH 2 ) 14 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:36);
  • Example 23 [A5c ⁇ , Om 33 (N-C(O)-(CH 2 ) 14 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:37);
  • Example 24 [A5c n , Om 43 (N-C(O)-(CH 2 ) 14 -CH 3 )]hGIP(l-43)-OH (SEQ ID NO:38);
  • Example 25 [A5c n , Cys 32 (succinimide-N-(CH 2 ) 15 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:39);
  • Example 26 [A5c ⁇ , Cys 33 (succinimide-N-(CH 2 ) 15 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:40);
  • Example 27 [A5c ⁇ , Cys 43 (succinimide-N-(CH 2 ) 15 -CH 3 )]hGIP(l-43)-OH (SEQ ID NO:41);
  • Example 28 (4HpPa 1 , Aib 2 , A5c 7 , Nle 14 )hGIP(l -3O)-NH 2 (SEQ ID NO:42);
  • Example 29 (4HpPa 1 , Aib 2 ' ⁇ , Nle I4 )hGIP(l -3O)-NH 2 (SEQ ID NO:43);
  • Example 30 (4HpPa 1 , Aib 2 , A5c 7 )hGIP(l -3O)-NH 2 (SEQ ID NO:44);
  • Example 31 -3 O)-NH 2 (SEQ ID NO:45);
  • Example 32 (4Hppa', Aib 2 , Nle 14 )hGIP(l -3O)-NH 2 (SEQ ID NO:46);
  • Example 35 (4HpPa 1 , hPro 3 , A6c 7 )hGIP(l-42)-OH (SEQ ID NO:49);
  • Example 36 (4HpPa 1 , Aib 2 , hPro 3 , Nle' 4 )hGIP(l -3O)-NH 2 (SEQ ID NO:50);
  • Example 37 (His 1 , Aib 2 13 , Nle 14 )hGIP(l-42)-OH (SEQ DD NO:51);
  • Example 38 (3,5Br-TyT 1 , Aib 2 ' 13 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:52);
  • Example 39 (His 1 , Aib 2 , A5c u , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:53);
  • Example 40 (3,5Br-TyT 1 , Aib 2 , A5c", Nle M )hGIP(l-42)-OH (SEQ ID NO:54);
  • Example 41 (3Cl-TyT 1 , Aib 2 , A5c ⁇ , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:55);
  • Example 42 (3Br-Tyr", Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ ID NO:56);
  • Example 43 (31-Tyr 1 , Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ ID NO:57);
  • Example 44 (3,51-Tyr 1 , Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ ID NO:58);
  • Example 45 (4NH 2 -PlIe 1 , Aib 2 , A5c u , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:59);
  • Example 46 (hTyr 1 , Aib 2 , A5c ⁇ , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:60);
  • Example 47 (Cpa 1 , Aib 2 , A5c n , Nle 14 )hGIP(l-42)-OH (SEQ ID N0:61);
  • Example 48 (4NH 2 CH 2 -PlIe 1 , Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ DD NO:62);
  • Example 50 (3F-PlIe 1 , Aib 2 , A5c ⁇ , Nle M )hGIP(l-42)-OH (SEQ ID NO:64);
  • Example 51 (3,4F-Phe', Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ ID NO:65);
  • Example 52 (3,5F-Phe', Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ ID NO:66);
  • Example 53 (3OH-Phe', Aib 2 , A5c"' 41 )hGIP(l-42)-OH (SEQ DD NO:67);
  • Example 54 (3OH-Tyr', Aib 2 , A5c 11 41 )hGIP(l-42)-OH (SEQ DD NO:68);
  • Example 55 (3MeO-TyT 1 , Aib 2 , A5c ⁇ ' 41 )hGff(l-42)-OH (SEQ ID NO:69);
  • Example 56 (Tyr(Ac) 1 , Aib 2 , A5c 11> 41 )hGIP(l-42)-OH (SEQ ID NO:70);
  • Example 58 (Tyr(Me) ⁇ Aib 2 , A5c" > 41 )hGIP(l-42)-OH (SEQ ID NO:72);
  • Example 60 (4PaI 1 , Aib 2 , A5c ⁇ ' 41 )hGIP(l-42)-OH (SEQ ID NO:74);
  • Example 61 (3PaI 1 , Aib 2 , A5c u ' 41 )hGIP(l-42)-OH (SEQ ID NO:75);
  • Example 62 (Taz 1 , Aib 2 , A5c 11 41 )hGIP(l-42)-OH (SEQ DD NO:76);
  • Example 63 (3NO 2 -TyT 1 , Aib 2 , A5c ⁇ ' 41 )hGIP(l-42)-OH (SEQ ED NO:77);
  • Example 64 (3TW 1 , Aib 2 , A5c ⁇ ' 41 )hGIP(l-42)-OH (SEQ ID NO:78);
  • Example 65 (4CN-Phe ⁇ Aib 2 , A5c ⁇ ' 41 )hGIP(l-42)-OH (SEQ DD NO:79);
  • Example 66 (3F-TyT 1 , GIy 2 , A5c ⁇ ' 40 )hGIP(l-42)-OH (SEQ DD NO:80);
  • Example 68 (3F-PlIe 1 , Aib 2 , A5c ⁇ ' 41 )hGD ) (l-42)-OH (SEQ DD NO:82);
  • Example 69 (3C1-Phe', Aib 2 , A5c ⁇ ' 41 )hGIP(l-42)-OH (SEQ DD NO:83);
  • Example 70 (3Br-Phe', Aib 2 , A5c u ' 41 )hGD ) (l-42)-OH (SEQ DD NO:84);
  • Example 71 (3Cl-TyT 1 , Aib 2 , A5c 11 41 )hGD > (l-42)-OH (SEQ DD NO:85);
  • Example 72 (3Br-TyT 1 , Aib 2 , A5c u - 41 )hGD > (l-42)-OH (SEQ DD NO:86);
  • Example 73 ( ⁇ -Tyr 1 , Aib 2 , A5c l ll 41 )hGIP(l-42)-OH (SEQ DD NO:87);
  • Example 74 Aib 2 , A5c 11 ' 41 )hGE ) (l-42)-OH (SEQ DD NO:88);
  • Example 75 (2F-Ty ⁇ ', Aib 2 , A5c 11> 41 )hGD > (l-42)-OH (SEQ DD NO:89);
  • Example 76 ( ⁇ Me-Tyr 1 , Aib 2 , A5c 11 41 )hGD > (l-42)-OH (SEQ DD NO:90);
  • Example 77 (3NH 2 -TyT 1 , Aib 2 , A5c ⁇ ' 41 )hGIP(l-42)-OH (SEQ DD NO:91);
  • Example 78 (2PaI 1 , Aib 2 , A5c"' 41 )hGIP(l-42)-OH (SEQ DD NO:92);
  • Example 79 [3(HO-CH 2 )TyT 1 , Aib 2 , A5c" 41 ]hGD > (l-42)-OH (SEQ DD NO:93);
  • Example 80 (2,6Me-TyT 1 , Aib 2 , A5c ⁇ , His 43 )hGD > (l-43)-OH (SEQ DD NO:94);
  • Example 81 (2,6Me-TyT 1 , Aib 2 , A5c Ul 14 , His 43 )hGD > (l-43)-OH (SEQ DD NO:95);
  • Example 82 (2,6Me-TyT 1 , Aib 2 , A5c u , NIe 14 , His 43 )hGIP(l-43)-OH (SEQ DD NO:96);
  • Example 83 (Ac-A6c 7 )hGIP(7-42)-OH (SEQ ID NO:97);
  • Example 85 [Ac-A6c 7 , Cys(Psu) 39 ]hGD > (7-42)-OH (SEQ DD NO:99);
  • Example 86 [Ac-A6c 7 , Cys(Psu) 38 ]hGIP(7-42)-OH (SEQ DD NO: 100);
  • Example 87 [Ac-A6c 7 , Cys(Psu) 36 ]hG ⁇ > (7-42)-OH (SEQ DD NO: 101);
  • Example 88 [Ac-A6c 7 , Cys(Psu) 35 ]hGD > (7-42)-OH (SEQ DD NO: 102);
  • Example 90 [Ac-A6c 7 , Cys(Psu) 33 ]hGD > (7-42)-OH (SEQ DD NO: 104);
  • Example 91 [Ac-A6c 7 , Cys(Psu) 32 ]hGIP(7-42)-OH (SEQ DD NO: 105);
  • Example 92 [Ac-A6c 7 , Cys(Psu) 31 ]hGIP(7-42)-OH (SEQ ID NO: 106);
  • Example 93 [Ac-A6c 7 , Cys(Psu) 37 ]hGIP(7-42)-OH (SEQ ID NO: 107);
  • Example 94 [Ac-A6c 7 , Orn 31 (N-C(O)-(CH 2 ) l2 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 108);
  • Example 95 [Ac-A6c 7 , Orn 31 (N-C(O)-(CH 2 ) 8 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO:109);
  • Example 96 [A6c 7 , Orn 31 (N-C(O)-(CH 2 ) 8 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 110);
  • Example 97 [CH 3 -(CH 2 ) 8 -C(O)-A6c 7 , Orn 31 (N-C(O)-(CH 2 ) 8 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 111);
  • Example 99 [A6c 7 , Orn 31 (N-C(O)-(CH 2 ) 4 -CH 3 )]hGIP(7-42)-0H (SEQ ID NO: 113);
  • Example 100 [CH 3 -(CH 2 ) 4 -C(O)-A6c 7 , Orn 31 (N-C(O)-(CH 2 ) 4 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 114);
  • Example 101 [Ac-A6c 7 , Orn 34 (N-C(O)-(CH 2 ) 8 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 115);
  • Example 102 [A6c 7 , Orn 34 (N-C(O)-(CH 2 ) 8 -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 116);
  • Example 103 [CH 3 -(CH 2 ) 8 -C(O)-A6c 7 , Orn 34 (N-C(O)-(CH 2 ) g -CH 3 )]hGIP(7-42)-OH (SEQ ID NO: 117);
  • Example 104 [Ac-A6c 7 , Cys(Hsu) 31 ]hGIP(7-42)-OH (SEQ ID NO: 118);
  • Example 105 [A6c 7 , Cys(Hsu) 31 ]hGIP(7-42)-OH (SEQ ID NO:119);
  • Example 106 (Ac-A6c 7 , 2Nal 31 )hGIP(7-42)-OH (SEQ ID NO: 120);
  • Example 107 (Ac-A6c 7 , D-2Nal 3I )hGIP(7-42)-OH;
  • Example 108 (Ac-4Hyp 3 , A6c 7 )hGIP(3-42)-OH (SEQ ID NO: 121);
  • Example 109 (Ac-A6c 7 , Gln 43 )hGIP(7-43)-OH (SEQ ID NO: 122);
  • Example 110 [Ac-A6c 7 , Cys(Psu) 31 ]hGIP(7-34)-NH 2 (SEQ ID NO: 123);
  • Example 111 [Ac-A6c 7 , Cys(Psu) 31 ]hGIP(7-31)-NH 2 (SEQ ID NO: 124);
  • Example 112 [Ac-Phe 6 , A6c 7 , Cys(Psu) 31 ]hGIP(6-42)-OH (SEQ ID NO: 125);
  • Example 113 [A6c 7 , Cys(Psu) 31 ]hGIP(6-42)-OH (SEQ DD NO: 126);
  • Example 114 (Ac-Phe 6 , A6c 7 )hGIP(6-30)-NH 2 (SEQ ID NO: 127);
  • Example 115 [Ac-Phe 6 , A6c 7 , Cys(Psu) 3l ]hGIP(6-31)-NH 2 (SEQ ID NO: 128);
  • Example 116 [A6c 7 , Cys(Psu) 31 ]hGIP(6-31)-NH 2 (SEQ ID NO:129);
  • Example 117 (A5c 7 , Nle l4 )hGIP(6-30)-NH 2 (SEQ ID NO: 130);
  • Example 118 (A6c 7 , Nle 14 )hGD?(6-30)-NH 2 (SEQ ID NO: 131);
  • Example 119 (Aib 11 , Nle 14 )hGIP(6-30)-NH 2 (SEQ ID NO: 132);
  • Example 120 [Ac-Asp 9 , Cys(Psu) 33 ]hGD?(9-42)-OH (SEQ ID NO: 133);
  • Example 121 [Orn 3l (N-C(O)-(CH 2 ) 8 -CH 3 )]hGIP(8-42)-OH (SEQ DD NO: 134);
  • Example 122 [Chc-Ser 8 , Cys(Psu) 31 ]hGIP(8-42)-OH (SEQ ID NO: 135);
  • Example 123 [CH 3 -(CH 2 ) 4 -C(O)-Ser 8 , Cys(Psu) 31 ]hGIP(8-42)-OH (SEQ ID NO: 136);
  • Example 124 (4Hppa 2 , 4Hyp 3 , A6c 7 )hGIP(2-42)-OH (SEQ ID NO: 137);
  • Example 125 (4Hppa 2 , Pro 3 , Nle M )hGIP(2-42)-OH (SEQ ID NO: 138);
  • Example 126 (4Hppa 2 , Aib 13 )hGEP(2-42)-OH (SEQ ID NO: 139);
  • Example 127 (4Hppa 2 , A6c 14 )hGIP(2-42)-OH (SEQ ID NO: 140);
  • Example 128 (4Hppa 2 , A6c ⁇ )hGIP(2-42)-OH (SEQ ID NO:141);
  • Example 129 (Aib 2 ' u )hGIP(l-42)-OH (SEQ ED NO: 142);
  • Example 130 (Aib 2 ' 9 )hGEP(l-42)-OH (SEQ ID NO:143);
  • Example 132 (Aib 2 ' 5 )hGIP(l-42)-OH (SEQ ID NO: 145);
  • Example 134 (Aib 2 , A5c 7 )hGEP(l -42)-OH (SEQ ID NO: 147);
  • Example 135 (Aib 2 , A5c 12 )hGIP(l-42)-OH (SEQ ID NO:148);
  • Example 136 (Aib 2 ' 12 )hGIP(l-42)-OH (SEQ ID NO: 149);
  • Example 137 (Aib 2 ' >GIP(l-42)-OH (SEQ ID NO: 150);
  • Example 138 (Aib 2 ' 4 )hGEP(l-42)-OH (SEQ ID NO:151);
  • Example 139 (Aib 2 , A5c 5 )hGIP(l -3O)-NH 2 (SEQ ID NO:152);
  • Example 140 (Aib 2 , A5c 7 )hGIP(l -3O)-NH 2 (SEQ ID NO:153);
  • Example 141 (Aib 2 , A5c 12 )hGEP(l -3O)-NH 2 (SEQ ID NO:154);
  • Example 142 (Aib 2 ' 4 )hGEP(l -3O)-NH 2 (SEQ ID NO: 155);
  • Example 143 (Aib 2 ' 5 )hGE?(l -3O)-NH 2 (SEQ ID NO: 156);
  • Example 144 (Aib 2 ' 7 )hGEP(l -3O)-NH 2 (SEQ ID NO: 157);
  • Example 145 (Aib 2 ' 8 )hGEP(l -3O)-NH 2 (SEQ ID NO: 158);
  • Example 146 (Aib 2 ' >GIP( 1-3 O)-NH 2 (SEQ ID NO: 159);
  • Example 148 (Aib 2 ' 12 )hGIP(l -3O)-NH 2 (SEQ LD NO:161);
  • Example 149 (Aib 2 ' 13 , A6c 7 , Nle 14 )hGIP(l-42)-OH (SEQ ED NO: 162);
  • Example 150 (Aib 2 ' 31 , A6c 7 )hGEP(l-42)-OH (SEQ ED NO: 163);
  • Example 151 (Aib 2 ' 41 , A6c 7 )hGEP(l-42)-OH (SEQ ID NO: 164);
  • Example 152 (Aib 2 ' 31 , A6c 7 , Nle M )hGEP(l-42)-OH (SEQ ED NO: 165);
  • Example 153 (Aib 2 ' 41 , A6c 7 , Nle 14 )hGEP(l-42)-OH (SEQ ED NO: 166);
  • Example 154 (Aib 2 , A6c 7 ' 26 , Nle 14 )hGEP(l-42)-OH (SEQ ED NO: 167);
  • Example 155 (Aib 2 , A6c 7 ' 27 , Nle 14 )hGEP(l-42)-OH (SEQ ED NO: 168);
  • Example 156 (Aib 2 , A6c 7 ' 40 , Nle 14 )hGEP(l-42)-OH (SEQ ED NO: 169);
  • Example 157 (Aib 2 , A6c 7 ' 41 , Nle 14 )hGEP(l-42)-OH (SEQ ED NO: 170);
  • Example 158 (Aib 2 ' 28 , A6c 7 , Nle 14 )hGEP(l-42)-OH (SEQ ED NO: 171);
  • Example 159 (Aib 2 , A6c 7 , NIe 14 )hGEP(l -3O)-NH 2 (SEQ ED NO: 172);
  • Example 160 (Aib 2 , A5c 7 , Nle 14 )hGEP(l-30)-NH 2 (SEQ ED NO:173);
  • Example 161 (Aib 2 ' ", Nle l4 )hGEP(l -3O)-NH 2 (SEQ ED NO:174);
  • Example 162 (A5c 2 ' 7 , Nle 14 )hGEP(l -3O)-NH 2 (SEQ ED NO: 175);
  • Example 163 (Aib 2 , A5c 7 ' 14 )hGIP(l -3O)-NH 2 (SEQ ID NO: 176);
  • Example 164 (A6c 2 ' ⁇ Nle I4 )hGIP(l -3O)-NH 2 (SEQ ID NO: 177);
  • Example 165 (Aib 2 , A6c 7 ' 17 , Nle I4 )hGIP(l-42)-OH (SEQ ID NO: 178);
  • Example 166 (Aib 2 11 , A6c 14 )hGIP(l -3O)-NH 2 (SEQ ED NO:179);
  • Example 167 (Aib 2 , A6c 7 ' 14 )hGD?(l -3O)-NH 2 (SEQ ID NO: 180);
  • Example 168 (A5c 2 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO: 181);
  • Example 169 (Aib 2 11 , A6c 14 )hGIP(l-42)-OH (SEQ ID NO: 182);
  • Example 170 (Aib 2 , A6c 14 )hGD?(l-42)-OH (SEQ DD NO: 183);
  • Example 171 (Aib 2 , A6c 7 )hGIP(l -42)-OH (SEQ ID NO: 184);
  • Example 172 (Aib 2 , A5c 7 , A6c 14 )hGB?(l-42)-OH (SEQ ID NO: 185);
  • Example 173 (Aib 2 11 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO: 186);
  • Example 175 (Aib 2 ' 13 )hGIP(l -3O)-NH 2 (SEQ ID NO: 188);
  • Example 176 (Aib 2 , A5c u , A6c 14 )hGIP(l -3O)-NH 2 (SEQ ID NO:189);
  • Example 177 (Aib 2 ' 13 , Nle 14 )hGIP(l -3O)-NH 2 (SEQ ID NO: 190);
  • Example 178 (Aib 2 , A5c ⁇ , Nle 14 )hGIP(l -3O)-NH 2 (SEQ ID NO: 191);
  • Example 179 (Aib 2 , A6c 7 ' 14 )hGIP(l-42)-OH (SEQ ID NO:192);
  • Example 180 (Aib 2 , A6c 7 )hGIP(l -3O)-NH 2 (SEQ ID NO: 193);
  • Example 181 (Aib 2 , A5c' ⁇ hGIP(I -42)-OH (SEQ ID NO:194);
  • Example 182 (Aib 2 , A5c", Nle 14 )hGIP(l-42)-OH (SEQ ID NO: 195);
  • Example 184 (A5c 2> 7 , A6c 14 )hGB?(l-42)-OH (SEQ ID NO: 197);
  • Example 185 (Aib 2 ' 13 , Nle 14 )hGD?(l-42)-OH (SEQ ID NO:198);
  • Example 186 (Aib 2 , A5c 7 , Nle 14 )hGC?(l-42)-OH (SEQ ID NO: 199);
  • Example 187 (Aib 2 , A5c 7 ' 14 )hGIP(l-42)-OH (SEQ ID NO:200);
  • Example 188 (Aib 2> l3 )hGD?(l-42)-OH (SEQ ID NO:201);
  • Example 189 (Aib 2 , A5c u , A6c 14 )hGIP(l-42)-OH (SEQ ID NO:202);
  • Example 190 (Pro 3 , Aib 13 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:203);
  • Example 191 (hPro 3 , Aib 13 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:204);
  • Example 192 (Dhp 3 , Aib 13 , Nle 14 )hGD?(l-42)-OH (SEQ ID NO:205);
  • Example 194 (Tic 3 , Aib 13 )hGIP(l-42)-OH (SEQ ID NO:207);
  • Example 196 (4Hyp ⁇ Aib 13 , Nle 14 )hGD?(l-42)-OH (SEQ ID NO:209);
  • Example 197 (Tic 3 , Aib 13 , Nle 14 )hGB?(l-42)-OH (SEQ ID NO:210);
  • Example 198 (3Hyp 3 , Aib 13 , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:211);
  • Example 199 (Tic 3 , A6c 14 )hGD?(l-42)-OH (SEQ ID NO:212);
  • Example 200 (hPro 3 , A6c 14 )hGIP(l-42)-OH (SEQ ED NO:213);
  • Example 201 [Aib 2 , A6c 7 , Cys(Psu) 41 ]hGIP(l-42)-OH (SEQ ID NO:214);
  • Example 202 (hPro 3 , A5c")hGIP(l-42)-OH (SEQ ID NO:215);
  • Example 203 (Pro 3 , Aib 13 )hGIP(l-42)-OH (SEQ ID NO:216);
  • Example 204 (Pro 3 , A5c 7 ' 14 )hGEP(l-42)-OH (SEQ ID NO:217);
  • Example 205 (Pro 3 , A5c")hGEP(l-42)-OH (SEQ ID NO:218);
  • Example 206 [Aib 2 , A6c 7 , Cys(Psu) 40 ]hGIP(l-42)-OH (SEQ ID NO:219);
  • Example 207 [Aib 2 , A6c 7 , Cys(Psu) 39 ]hGD?(l-42)-OH (SEQ ID NO:220);
  • Example 208 [Aib 2 , A6c 7 , Cys(Psu) 38 ]hGIP(l-42)-OH (SEQ ID NO:221);
  • Example 209 [Aib 2 , A6c 7 , Cys(Psu) 36 ]hGIP(l-42)-OH (SEQ ID NO:222);
  • Example 210 (Tic 3 , A5c ⁇ )hGIP(l-42)-OH (SEQ ID NO:223);
  • Example 211 (hPro 3 , A5c u , A6c 14 )hGD?(l-42)-OH (SEQ ID NO:224);
  • Example 212 (4Hyp 3 , A6c 14 )hGB?(l-42)-OH (SEQ ID NO:225);
  • Example 213 [Aib 2 , A6c 7 , Cys(Psu) 35 ]hGIP(l-42)-OH (SEQ ID NO:226);
  • Example 214 [Aib 2 , A6c 7 , Cys(Psu) 34 ]hGIP(l-42)-OH (SEQ ID NO:227);
  • Example 216 (4Hyp 3 , A5c u , A6c 14 )hGIP(l-42)-OH (SEQ ID NO:229);
  • Example 217 (Tic 3 , A5c ⁇ , A6c 14 )hGEP(l-42)-OH (SEQ ID NO:230);
  • Example 218 [Aib 2 , A6c 7 , Cys(Psu) 31 ]hGEP(l-42)-OH (SEQ ID NO:231);
  • Example 219 (Pro 3 , A6c 14 )hGEP(l-42)-OH (SEQ ED NO:232);
  • Example 220 (Pro 3 , A5c ⁇ , Nle 14 )hGIP(l-42)-OH (SEQ ID NO:233);
  • Example 221 (Aib 2 , A6c 7 , Gln 43 )hGD?(l-43)-OH (SEQ DD NO:234);
  • Example 222 [Aib 2 , A5c 7 , Cys(Psu) 32 ]hGIP(l-42)-OH (SEQ ID NO:235);
  • Example 223 [Aib 2 , A5c 7 , Cys(Psu) 43 ]hGD?(l-43)-OH (SEQ ID NO:236);
  • Example 224 (Pro 3 , A5c", A6c 14 )hGEP(l-30)-NH 2 (SEQ ID NO:237);
  • Example 225 (Pro 3 , A6c 7 )hGIP(l -3O)-NH 2 (SEQ ED NO:238);
  • Example 226 (Pro 3 , A5c")hGIP(l -3O)-NH 2 (SEQ ED NO:239);
  • Example 227 [Aib 2 , A6c 7 , Cys(Psu) 33 ]hGEP(l-42)-OH (SEQ ED NO:240);
  • Example 228 [Aib 2 , A6c 7 , Cys(Psu) 37 ]hGEP(l-42)-OH (SEQ ED NO: 241);
  • Example 229 (4Hppa', Aib 13 )hGEP(l-42)-OH (SEQ ED NO:242);
  • Example 230 (Pro 3 , A5c", A6c M )hGEP(l-42)-OH (SEQ ED NO:243);
  • Example 231 [Orn'(N-C(O)-(CH 2 ) l2 -CH3), A6c 7 ]hGEP(l-42)-OH (SEQ ED NO:244);
  • Example 232 (D-AIa 2 , A5c n ' 40 )hGEP(l-42)-OH;
  • Example 233 (D-AIa 2 , A5c", His 43 )hGEP(l-43)-OH;
  • Example 234 (D-AIa 2 , A5c"' 41 )hGEP(l-42)-OH;
  • Example 235 (D-AIa 2 , A6c"' l4 ' 41 )hGEP(l-42)-OH;
  • Example 236 (Aib 2 ' 13 , Pro 3 , Nle M )hGEP(l -3O)-NH 2 (SEQ ED NO:245);
  • Example 237 (Aib 2 , Pro 3 , A6c 7 )hGIP( 1-3 O)-NH 2 (SEQ ID NO:246);
  • Example 238 (Aib 2 , Pro 3 , A5c ⁇ )hGIP(l-30)-NH 2 (SEQ ID NO:247);
  • Example 239 (Aib 2 , Pro 3 , A5c", Nle 14 )hGIP(l -3O)-NH 2 (SEQ ID NO:248);
  • Example 240 (Aib 2 , Pro 3 , A5c u , A6c 14 )hGIP(l-30)-NH 2 (SEQ ID NO:249);
  • Example 241 (NMe-Tyr 1 , Aib 2 , A5c ⁇ , Nle I4 )hGIP(l-42)-OH (SEQ ID NO:250);
  • Example 242 (GIy 2 , A6c"' 14 41 )hGIP(l-42)-OH (SEQ ID NO:251);
  • Example 243 (GIy 2 , Aib 13 , A5c 40 )hGIP(l-42)-OH (SEQ ID NO:252);
  • Example 244 (GIy 2 , A5c u ' 41 )hGIP(l-42)-OH (SEQ ID NO:253);
  • Example 245 (GIy 2 , A5c ⁇ , His 43 )hGIP(l-43)-OH (SEQ ID NO:254);
  • Example 246 (3F-PlIe 1 , Aib 2 , A5c ⁇ > 14> 41 )hGIP(l-42)-OH (SEQ ID NO:255);
  • Example 247 (3F-Phe ⁇ Aib 2 , A5c 11 41 , NIe 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:256);
  • Example 248 (3F-Phe', Aib 2 , A5c Ul 41 , His 43 )hGIP(l-43)-OH (SEQ ID NO:257);
  • Example 249 (3F-Phe', Aib 2 , A5c u ' 14 41 , His 43 )hGIP(l-43)-OH (SEQ ID NO:258);
  • Example 250 deleted Example 251: (GIy 2 , A5c ⁇ , NIe 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:259);
  • Example 252 (D-AIa 2 , A5c u , NIe 14 , His 43 )hGIP(l-43)-OH;
  • Example 253 (D-AIa 2 , A5c ⁇ > 14 , His 43 )hGIP(l-43)-OH;
  • Example 254 (D-AIa 2 , A5c ⁇ > 14 )hGIP(l -3O)-NH 2 ;
  • Example 255 (D-AIa 2 , A5c ⁇ , His 31 )hGIP(l-31)-NH 2 ;
  • Example 256 (Aib 2 , A5c 11> 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:260);
  • Example 257 (A5c ⁇ )hGIP(l -3O)-NH 2 (SEQ ID NO:261);
  • Example 258 (A5c ⁇ , His 3 ⁇ hGIP(I -31)-NH 2 (SEQ ID NO:262);
  • Example 259 (A5c ⁇ ' 14 )hGIP(l -3O)-NH 2 (SEQ ID NO:263);
  • Example 260 (A5c ⁇ ' 41 , Cys 32 )hGIP(l-42)-NH 2 (SEQ ID NO:264);
  • Example 261 (A5c ⁇ ' 41 , Cys 33 )hGIP(l-42)-NH 2 (SEQ ID NO:265);
  • Example 262 (A5c 11 41 , Cys 43 )hGIP(l-43)-NH 2 (SEQ ID NO:266);
  • Example 263 [A5c ⁇ , Orn 32 (N-C(O)-(CH 2 ) 10 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:267);
  • Example 264 [A5c ⁇ , Orn 33 (N-C(O)-(CH 2 ) 10 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:268);
  • Example 265 [A5c ⁇ , Lys 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGIP(l-43)-OH (SEQ ID NO:269);
  • Example 266 [A5c", Cys 32 (succinimide-N-(CH 2 ) ⁇ -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:270);
  • Example 267 [A5c ⁇ , Cys 33 (succinimide-N-(CH 2 ) ⁇ -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:271);
  • Example 268 [A5c ⁇ , Cys 43 (succinimide-N-(CH 2 ) ⁇ r CH 3 )]hGIP(l-43)-OH (SEQ ID NO:272);
  • Example 269 [A5c ⁇ , Lys 43 (N-C(O)-(CH 2 ) 14 -CH 3 )]hGIP(l-43)-OH (SEQ ID NO:273);
  • Example 270 [A5c ⁇ , Om 32 (N-C(O)-(CH 2 ) 14 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:274);
  • Example 271 [A5c ⁇ , Orn 33 (N-C(O)-(CH 2 ) 14 -CH 3 ), His 43 ]hGIP(l-43)-OH (SEQ ID NO:275);
  • Example 272 (3C1-Tyr', D-AIa 2 , A5c", NIe 14 , His 43 )hGIP(l-43)-OH;
  • Example 273 (3Cl-TyT 1 , D-AIa 2 , A5c"' M , His 43 )hGIP(l-43)-OH;
  • Example 274 (3Cl-TyT 1 , Aib 2 , A5c u ' 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:276);
  • Example 275 (3Cl-TyT 1 , Aib 2 , A5c", NIe 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:277);
  • Example 276 [3C1-Tyr ⁇ Aib 2 , A5c n , NIe 14 , Orn 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGIP(l-43)-OH
  • Example 278 [3Cl-TyT 1 , D-AIa 2 , A5c", NIe 14 , Orn 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGIP(l-43)-OH;
  • Example 279 [3Cl-TyT 1 , D-AIa 2 , A5c ⁇ , NIe 14 , Cys 43 (succinimide-N-(CH 2 ) 11 -CH 3 )]hGIP(l-43)-OH;
  • Example 280 [3Cl-TyT 1 , D-AIa 2 , A5c"' 14 , Orn 43 (N-C(0)-(CH 2 ),o-CH 3 )]hGIP(l-43)-OH;
  • Example 281 [3Cl-TyT 1 , D-AIa 2 , A5c u> 14 , Cys 43 (succinimide-N-(CH 2 ) ⁇ -CH 3 )]hGIP(l-43)-OH;
  • Example 282 (3Br-TyT 1 , Aib 2 , A5c ⁇ , NIe 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:280);
  • Example 283 (3Br-TyT 1 , Aib 2 , A5c u ' 14 , His 43 )hGIP(l-43)-OH (SEQ ID NO:281);
  • Example 284 (3MeO-TyT 1 , Aib 2 , A5c u , His 43 )hGIP(l-43)-OH (SEQ ID NO:282);
  • Example 285 (3MeO-TyT 1 , Aib 2 , A5c u ' 14 , His 43 )hGIP(l-43)-OH (SEQ ED NO:283);
  • Example 286 (3MeO-TyT 1 , Aib 2 , A5c ⁇ ' 14 ' 41 , His 43 )hGIP(l-43)-OH (SEQ ID NO:284);
  • Example 287 (4CF 3 -PlIe 1 , Aib 2 , A5c ⁇ , His 43 )hGIP(l-43)-OH (SEQ ID NO:285);
  • Example 288 (7HO-Tic ! , Aib 2 , A5c", His 43 )hGIP(l-43)-OH (SEQ ID NO:286);
  • Example 290 (4CN-PlIe 1 , Aib 2 , A5c ⁇ , His 43 )hGIP(l-43)-OH (SEQ ID NO:288);
  • Example 291 (hTyr 1 , Aib 2 , A5c u , His 43 )hGIP(l-43)-OH (SEQ ID NO:289);
  • Example 292 [3Cl-TyT 1 , D-AIa 2 , A5c ⁇ , NIe 14 , Lys 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGIP(l-43)-OH;
  • Example 293 [3Cl-TyT 1 , D-AIa 2 , A5c Ml 14 , Lys 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGIP(l-43)-OH;
  • Example 294 [3Cl-TyT 1 , Aib 2 , A5c ⁇ , NIe 14 , Lys 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGIP(l-43)-OH
  • Example 296 [3C1-Ty ⁇ ', Aib 2 , A5c ⁇ , NIe 14 , Cys 43 ]hGEP(l-43)-OH (SEQ ID NO:293);
  • Example 297 [3Cl-TyT 1 , D-AIa 2 , A5c", NIe 14 , Cys 43 (succinimide)]hGIP(l-43)-OH;
  • Example 298 [3Cl-TyT 1 , D-AIa 2 , A5c"' 14 , Cys 43 (succinimide)]hGIP(l-43)-OH; and
  • Example 299 [Aib 2 , A5c n , NIe 14 , Lys 43 (N-C(O)-(CH 2 ) 10 -CH 3 )]hGEP(2-43)-OH (SEQ ID NO:294).
  • the present invention is not in any way limited to the above particularly preferred novel analogues of GEP.
  • the present invention encompasses a pharmaceutical composition comprising (Pro 3 )GEP(l-42) (SEQ ED NO:9) disclosed in PCT Pub. No. WO 00/58360, and all other analogues of GEP specifically disclosed is the above-discussed PCT Pub. No. WO 00/58360, PCT Pub. No. WO 98/24464, and PCT Pub. No. WO 03/082898.
  • the present invention encompasses the above illustrated GIP compounds which further comprise a covalently linked PEG moiety, in which said PEG moiety is covalently linked to the compound via a Cys(maleimide), hCys(maleimide), or Pen(maleimide) linker, to form Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG), wherein "succinimide-N-PEG” is either linear or branched as defined hereinbelow.
  • Such PEG moiety has average molecular weight of from about 2,000 to about 80,000, and preferably such PEG moiety is selected from the group consisting of 5K PEG, 1OK PEG, 2OK PEG, 30K PEG, 4OK PEG, 50K PEG, and 6OK PEG, to form Cys(succinimide-N-5K PEG), Cys(succinimide-N-10K PEG), Cys(succinimide-N-20K PEG), Cys(succinimide-N-30K PEG), Cys(succinimide-N-40K PEG), Cys(succinimide-N-50K PEG), Cys(succinimide-N-60K PEG), hCys(succinimide-N-5K PEG), hCys(succinimide-N-10K PEG), hCys(succinimide-N-20K PEG), hCys(succinimide-N-30K PEG), h
  • PEGylation occurs at any one of amino acid residue positions 16, 30, and 31-43, and preferably at any one of amino acid residue positions 32, 33 and 43, whereby Cys(succinimide-N- PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of such amino acid residue positions.
  • Cys(succinimide-N- PEG), hCys(succinimide-N-PEG), or Pen(succinimide-N-PEG) is placed in any one of such amino acid residue positions.
  • the above formula (I) may be expanded to provide PEGylation sites at positions A 44 -
  • the C-terminus of such PEGylated compounds of the present invention may be amidated, e.g., (Aib 2 ' ") hGIP(l-42)-NH 2 (SEQ ID NO:292), or it may remain as free acid, e.g., (Aib 2 ' ⁇ )hGIP(l-42)- OH (SEQ ID NO: 142).
  • the present invention is directed to a pharmaceutical composition of a clear aqueous solution, or a gel or a semi-solid, comprising the native GDP, a fragment thereof, an analogue of GIP, or a pharmaceutically acceptable salt thereof (which are collectively referred to as "GD? peptide” or "GIP compound”), in which the aqueous solution of the GD? peptide forms a precipitate after subcutaneous or intramuscular administration to a subject.
  • GD? peptide an analogue of GIP
  • GIP compound a pharmaceutically acceptable salt thereof
  • GIP is any one of the above-listed Examples 1 to 295, hGIP(l-42)-NH 2 (SEQ DD NO:2), hGIP(l-30)-NH 2 (SEQ ID NO:3), hGIP(l-30)-OH (SEQ ID NO:4), hGIP(7-30)-NH 2 (SEQ ID NO:5), hGIP(7-30)-OH (SEQ ID NO:6), hGIP(6-30)-NH 2 (SEQ DD NO:7), hGIP(6-30)-OH (SEQ ID NO:8), (Pro 3 )hGIP(l-42)-OH (SEQ DD NO:9), (Pro 3 )hGD>(l- 42)-NH 2 (SEQ DD NO: 10), (Aib 2 )hG ⁇ > (l-42)-OH (SEQ DD NO: 11), (Aib 2 )hGD>(l-42)- NH 2 (SEQ ID NO: 12), (D-Ala 2
  • composition according to paragraph 3 wherein said composition contains a divalent metal salt selected from the group consisting Of ZnCl 2 , ZnAc 2 , (C 6 H 5 Ov) 2 Zn 3 , CuCl 2 , CuAc 2 , (C 6 H 5 O 7 ) 2 Cu 3 , MgCl 2 , MgAc 2 , (C 6 H 5 O 7 ) 2 Mg 3 , CaCl 2 ,
  • FIG. 1 shows the full time course plot of the pharmacokinetic profile (median values) obtained after a single subcutaneous administration to Sprague Dawley rats dosed at 0.9 mg/rat (6 ⁇ l of 15% solution) with the molar ratio of the peptide of Example 2 to ZnCl 2 of 0.5:1.
  • FIG. 2 shows the estimated percentage of Example 2 remaining at the injection site of Sprague Dawley rats after a single subcutaneous administration of the test formulation shown in FIG. 1.
  • FIG. 3 shows the full time course plot of the pharmacokinetic profile (median values) obtained after a single subcutaneous administration to Sprague Dawley rats dosed at 0.9 mg/rat (6 ⁇ l of 15% solution) with the molar ratio of the peptide of Example 3 to ZnCl 2 of 0.5: 1.
  • FIG. 4 shows the estimated percentage of Example 3 remaining at the injection site of Sprague Dawley rats after a single subcutaneous administration of the test formulation shown in FIG. 3.
  • FIG. 5 shows the in vivo effects of the compounds of Examples 1-7 and the native GIP on insulin release of Sprague Dawley rats.
  • A4c 1 -amino- 1 -cyclobutanecarboxylic acid
  • A5c 1 -amino- 1 -cyclopentanecarboxylic acid
  • A6c 1 -amino- 1 -cyclohexanecarboxylic acid
  • Ado 12-aminododecanoic acid
  • Aib ⁇ -aminoisobutyric acid
  • Aic 2-aminoindan-2 -carboxylic acid
  • Aun 11-aminoundecanoic acid
  • Ava 5-aminovaleric acid
  • Cys or C cysteine
  • D-AIa D-alanine
  • valine other abbreviations used herein are defined as follows:
  • Boc tert-butyloxycarbonyl
  • BSA bovine serum albumin
  • DIPEA diisopropylethyl amine
  • HBTU 2-( 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate
  • PBS phosphate buffered saline 5K
  • PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 5,000
  • 1OK PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 10,000
  • 2OK PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 20,000
  • 3OK PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 30,000
  • 4OK PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 40,000
  • 50K PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 50,000
  • 6OK PEG polyethylene glycol, which may include other functional groups or moieties such as a linker, and which is either linear or branched as defined hereinbelow, with an average total molecular weight of about 60,000 tBu: tert-buty ⁇
  • the Greek letter psi " ⁇ " is used herein to indicate that a peptide bond has been replaced by a pseudopeptide bond.
  • the format of the ⁇ term is A'- ⁇ -(X-X')A 2 wherein A 1 is the amino acyl radical whose carbonyl group has been modified to X and A 2 is the amino acyl radical whose ⁇ -amino group has been modified to X'.
  • X and X 1 are shown as strings of element symbols separated by a bond, e.g. , Tyr- ⁇ -(CH 2 -NH)Gly.
  • Cys(succinimide-N-alkyl) has the structure of:
  • Cys(Hsu) has the structure of:
  • Pen(succinimide-N-(CH 2 ) x -C(O)-NH-(CH 2 ) y -CH 3 ) has the structure of:
  • PenCsuccinimide-N-PEG has the structure of: "Cys(succinimide-N-(CH 2 ) 2 -C(O)NH-(CH 2 ) 3 -PEG)” has the structure of:
  • (Ci-C 30 )hydrocarbon moiety encompasses alkyl, alkenyl and alkynyl, and in the case of alkenyl and alkynyl there are C 2 -C 30 .
  • a peptide of this invention is also denoted herein by another format, e.g., (A5c 2 )hGEP(l-42)- OH (SEQ ID NO:295), with the substituted amino acids from the natural sequence placed between the brackets (e.g., A5c 2 for Ala 2 in hGIP).
  • the numbers between the parentheses refer to the number of amino acids present in the peptide (e.g., hGIP(l-42)-OH (SEQ ED NO:1) is amino acids 1 through 42 of the peptide sequence for hGIP).
  • hGIP(l -3O)-NH 2 indicates that the C-terminus of the peptide is amidated; hGIP(l-42) (SEQ ID NO:1) or hGIP(l-42)- OH (SEQ ID NO:1) means that the C-terminus is the free acid.
  • hGIP Human GIP
  • Alkyl refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl.
  • R is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl.
  • Alkyl refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight- chain or contain one or more branches or cyclic groups.
  • Substituted alkyl refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH 2 , -NHCH 3 , -NO 2 , -Ci -20 alkyl substituted with halogens, -CF 3 , -OCH 3 , -OCF 3 , and -(CH 2 ) 0 - 20 -COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of-(CH 2 ) 0 .
  • halogen i.e., fluorine, chlorine, bromine, and iodine
  • alkyl acids containing, or consisting of, -(CH 2 ) 0-20 -COOH include 2-norbomane acetic acid, tert-butyric acid and 3-cyclopentyl propionic acid.
  • Heteroalkyl refers to an alkyl wherein one of more of the carbon atoms in the hydrocarbon group are replaced with one or more of the following groups: amino, amido, -O-, -S- or carbonyl. In different embodiments 1 or 2 heteroatoms are present.
  • Substituted heteroalkyl refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, -OH, -CN, -SH, -NH 2 , -NHCH 3 , -NO 2 , -Ci -20 alkyl substituted with halogens, -CF 3 , -OCH 3 , -OCF 3 , and -(CH 2 ) 0-20 -COOH. In different embodiments 1, 2, 3 or 4 substituents are present.
  • alkenyl refers to a hydrocarbon group made up of two or more carbons wherein one or more carbon-carbon double bonds are present.
  • the alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
  • Substituted alkenyl refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen, -OH, -CN, -SH, -NH 2 , -NHCH 3 , -NO 2 , -C 1-20 alkyl substituted with halogens, -CF 3 , -OCH 3 , -OCF 3 , and -(CH 2 V 20 -COOH. In different embodiments 1, 2, 3 or 4 substituents are present.
  • Aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to three conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
  • the aryl is a 5 or 6 membered ring.
  • Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and/or nitrogen.
  • Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and 9-anthracene.
  • Aryl substituents are selected from the group consisting Of-C 1-20 alkyl, -C 1-2 O alkoxy, halogen, -OH, -CN, -SH, -NH 2 , -NO 2 , -C 1-20 alkyl substituted with halogens, -CF 3 , -OCF 3 , and - (CH 2 )o -20 -COOH.
  • the aryl contains O, 1,2, 3, or 4 substituents.
  • Alkylaryl refers to an “alkyl” joined to an “aryl”.
  • the peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J. M., et al, 1984, Solid Phase Synthesis, Pierce Chemical Co., 2d ed.
  • the following examples describe synthetic methods for making a peptide of this invention, which methods are well- known to those skilled in the art. Other methods are also known to those skilled in the art. The examples are provided for the purpose of illustration and are not meant to limit the scope of the present invention in any manner.
  • Example 15 rA6c 7 . CvsfPsuV 2 lhGIPq-42VOH
  • Solid-phase peptide synthesis was used to assemble the peptide using microwave-assisted Fmoc Chemistry on a Liberty Peptide Synthesizer (CEM; Matthews, NC, USA) at the 0.1 mmole scale.
  • Pre-loaded Fmoc-Cys(Trt)-Wang resin (0.59 mmole/g; Novabiochem, San Diego, CA, USA) was used to generate the C-terminal acid peptide.
  • the resin (0.17 g) was placed in a 50 ml conical tube along with 15 ml of dimethylformamide (DMF) and loaded onto a resin position on the synthesizer. The resin was then quantitatively transferred to the reaction vessel via the automated process.
  • DMF dimethylformamide
  • the standard Liberty synthesis protocol for 0.1 mmole scale synthesis was used. This protocol involves deprotecting the N-terminal Fmoc moiety via an initial treatment with 7 ml of 20% piperidine, containing 0.1M N-hydroxybenzotriazole (HOBT), in DMF. The initial deprotection step was for 30 seconds with microwave power (45 watts, maximum temperature of 75 0 C), and nitrogen bubbling (3 seconds on / 7 seconds off). The reaction vessel was then drained and a second piperidine treatment, identical to the first treatment, except that it was for a 3 -minute duration. The resin was then drained and thoroughly washed with DMF several times.
  • HOBT N-hydroxybenzotriazole
  • the protected amino acid, Fmoc- Thr(tBu)-OH prepared as 0.2M stock solution in DMF, was then added (2.5 ml, 5 eq.), followed by 1.0 ml of 0.45M (4.5 eq.) HBTU [2-(lH-benzo-triazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosaphate] in DMF. This was followed by the addition of 0.5 ml of 2M (10 eq.) DEPEA (diisopropylethyl amine) in NMP (N-methylpyrrollidinone). The coupling step was performed for 5 minutes using 20 watts of microwave power, a max temperature of 75 0 C, and the same rate of nitrogen bubbling.
  • Cycle 2 was then initiated similar to cycle 1. All amino acids were introduced similarly and a double-coupling strategy was employed throughout the entire sequence. Cycles 1-3, 19-20, 25-26, and 30-39 contained a capping procedure immediately following the coupling step. Capping was performed by adding 7 ml of 0.5M acetic anhydride, containing 0.015M HOBT in NMP, along with 2 ml of the 2M DIPEA solution using a multi-step microwave protocol: 50 watts of power for 30 seconds (65 0 C max temperature), followed by 30 seconds of microwave power off, followed by a second round of 30 seconds of microwave power on (50 watts), and then again 30 seconds of no microwave power.
  • a multi-step microwave protocol 50 watts of power for 30 seconds (65 0 C max temperature), followed by 30 seconds of microwave power off, followed by a second round of 30 seconds of microwave power on (50 watts), and then again 30 seconds of no microwave power.
  • Cycle 1 Fmoc-Thr(OtBu)-OH
  • Cycle 2 Fmoc-Ile-OH
  • Cycle 3 Fmoc-Asn(Trt)-OH
  • Cycle 4 Fmoc-His(Trt)-OH
  • Cycle 5 Fmoc- Lys(Boc)-OH
  • Cycle 6 Fmoc-Trp(Boc)-OH
  • Cycle 7 Fmoc-Asp(OtBu)-OH
  • Cycle 8 Fmoc- Asn(Trt)-OH
  • Cycle 9 Fmoc-Lys(Boc)-OH
  • Cycle 10 Fmoc-Lys(Boc)-OH
  • Cycle 11 Fmoc-Gly-OH
  • Cycle 12 Fmoc-Lys(Boc)-OH
  • Cycle 13 Fmoc-Gly-OH
  • Cycle 12 Fmoc-Lys(Boc)-OH
  • Cycle 13 Fmoc-Gly-OH
  • Cycle 35 Fmoc-Phe-OH; Cycle 36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; Cycle 37: Fmoc-Glu(OtBu)-OH; Cycle 38: Fmoc-Ala-OH; and Cycle 39: Fmoc-Tyr(tBu)-OH.
  • the coupling protocol for Fmoc-His(Trt)-OH was a slightly modified version of the standard protocol. The microwave power was off for the first 2 minutes, followed by 4 minutes with microwave power on (20 watts; max temperature of 50 0 C). Once the peptide backbone was complete, standard piperidine treatment was used to remove the N- terminal Fmoc group.
  • the resin was then thoroughly washed with DMF and then transferred back to the 50 ml conical tube using DMF as the transfer solvent.
  • the resin was deprotected and cleaved from the resin via treatment with 5 ml of the following reagent: 5% TIS, 2% water, 5% (w/v) dithiothrieitol (DTT), 88% TFA, and allowed to mix for 3.5 hours.
  • the filtrate was collected into 45 ml of cold anhydrous ethyl ether.
  • the precipitate was pelleted for 10 minutes at 3500 RPM in a refrigerated centrifuge.
  • the ether was decanted, and the peptide re-suspended in fresh ether.
  • the ether workup was performed a total of 2 times.
  • peptide was allowed to air dry to remove residual ether.
  • the peptide pellet was resuspended in 8 ml of acetonitrile (Acn) followed by 8 ml of de-ionized water, and allowed to fully dissolve.
  • the peptide solution was then analyzed by mass spectrometry. Mass analysis employing electrospray ionization identified a main product containing a mass of 4970.7 da; corresponding to the linear product.
  • the crude product (approximately 500 mg) was analysed by HPLC, employing a 250 x 4.6mm Cl 8 column (Phenomenex; Torrance, CA, USA) using a gradient of 2-80% acetonitrile (0.1% TFA) over 30 minutes.
  • the crude peptide was then derivatized with N-propylmaleimide (Pma) to generate the propylsuccinimide (Psu) derivative on the Cysteine side chain.
  • the crude linear peptide was brought up in water, adjusted to pH 6.5 with ammonium carbonate, at 5 mg/ml. Five equivalents of Pma was added with constant stirring for 30 seconds. Excess Pma was quenched using 5 eq. of dithiothreitol (DTT).
  • DTT dithiothreitol
  • the derivatized peptide solution was then analyzed by mass spectrometry. Mass analysis identified a main product containing a mass of 5109.7 da; corresponding to the desired Psu derivatized product.
  • the product was then purified via preparative HPLC using a similar gradient as before.
  • the purified product was analyzed by HPLC for purity (96.60%) and mass spectrometry (5108.9 Daltons) and subsequently lyophilized. Following lyophillization, 10.3 mg of purified product was obtained representing a 2% yield.
  • the PEGylated GIP compounds disclosed herein can be synthesized substantially according to the procedure described for the synthesis of the compound of Example 15, by using PEG- maleimide as the starting material instead of N-propylmaleimide used in Example 15.
  • Membranes for in vitro receptor binding assays were prepared by homogenizing the CHO-Kl clonal cells expressing the human recombinant GIP receptor, with a Brinkman Polytron (setting 6, 15 sec), in ice-cold 50 mM Tris-HCl and then subjected to two centrifugations at 39,000 g for 10 minutes with a resuspension in fresh buffer in between.
  • aliquots of the washed membrane preparations were incubated (100 minutes at 25 0 C with 0.05 nM [ 125 I]GIP (approximately 2200 Ci/mmol) in 5OmM Tris-HCl, O.lmg/ml bacitracin, and 0.1% BSA.
  • the final assay volume was 0.5 ml.
  • the incubations were terminated by rapid filtration through GF/C filters (pre-soaked in 0.5% polyethylenimine) using a Brandel filtration manifold. Each tube and filter were then washed three times with 5-ml aliquots of ice-cold buffer. Specific binding was defined as the total radioligand bound minus that bound in the presence of 1000 nM GIP.
  • Table 2 In vitro hGIP receptor binding data for the compounds exemplified herein are given in Table 2.
  • GlP peptide 50 ⁇ L 1 mg/mL was added to 450 ⁇ L plasma (human or rat), vertexed briefly and incubated at 37 0 C. 50 ⁇ L was removed at various times, like at 0, 1, 2, 3, 4, 8, 24, 32, 48, 56, 72 hours, mixed with 5 ⁇ L formic acid and 150 ⁇ L acetonitrile in a microcentrifuge tube, vertexed, and centrifuged for 10 minutes at 1OK rpm. The supernatant was transferred to an injection vial and analyzed by LC-MS.
  • the LC-MS system consisted of an API4000 mass spectrometer with an ESI probe. Positive ion mode and full scan detection were used.
  • HPLC separation was carried out on a Luna 3 ⁇ C8 (2), 2 x 30 mm column with a gradient from 90% A to 90% B in 10 minutes at a flow rate of 0.3 ml/min.
  • Buffer A was 1% formic acid in water and buffer B was 1% formic acid acetonitrile.
  • Human and rat plasma half-life data for the compounds exemplified herein are given in Table 2.
  • mice Male Sprague Dawley rats with a body weight of approximately 275-300 g were used as experimental subjects. The day prior to the treatment, right atrial cannulae were implanted via the jugular vein under chlorohydrate. Each cannula was filled with 100 u/ml heparin saline and tied. The rats were fasted for approximately 18 hours prior to dosing with the compound or the vehicle (saline/0.25% BSA). The day of the experiment, aliquots of compound were thawed, brought to room temperature and vortexed thoroughly. A careful check was made for any sign of compound coming out of solution.
  • a 500- ⁇ l blood sample was withdrawn and replaced with an equal volume of heparinized saline (10 u/ml).
  • a 500- ⁇ l blood sample was withdrawn through the cannula.
  • either the vehicle or the appropriate dose of the compound was injected into the cannula and pushed in with the glucose (1 g/kg) or vehicle solution.
  • 500 ⁇ l of volume of heparinized saline (10 u/ml) was used to push in the remaining glucose through the cannula.
  • FIG. 5 shows the in vivo effects of the compounds of Examples 1-7 and the native GIP on insulin release of Sprague Dawley rats. Numerical values of the total insulin secretion shown in FIG. 5 are summarized in Table 3. In addition, the in vivo effects of the compounds of Examples 20, 41, 55, 233, 234, 251 , and 252 were determined in separate tests under the identical experimental conditions as described above, and numerical values of the total insulin secretion for the compounds of Examples 20, 41, 55, 233, 234, 251, and 252 are summarized in Table 4.
  • the cloudy solution was centrifuged and the supernatant was injected for HPLC analysis.
  • a Luna 3 ⁇ C18(2) 4.6 x 100 mm column was run from 95% A (0.1% TFA water) to 80% B (0.1% TFA acetonitrile) in 30 minutes at a flow rate of 1 ml/min at room temperature.
  • UV detector was set at 220 nm.
  • a standard calibration curve was generated to calculate the concentration of the peptide in the solution, which was reported as the solubility of the peptide in the corresponding buffer. The results are listed in Table 5.
  • Peptide Samples Formulations of Examples 2 and 3 were prepared by using the following procedures.
  • the molar ratio of the peptide of Example 2 to ZnCl 2 is 0.5: 1.
  • the peptide concentration is 15% in water (w/v) with pH of about 3, which can be adjusted by using NaOH or HCl aqueous solutions.
  • the molar ratio of the peptide of Example 3 to ZnCl 2 is 0.5: 1.
  • the peptide concentration is 15% in water (w/v) with pH of about 3 , which can be adjusted by using NaOH or HCl aqueous solutions.
  • Sprague Dawley rats were dosed at 0.9 mg/rat (6 ⁇ l of 15% solution) subcutaneously with these peptide formulations. Blood samples were collected at 5, 10, 15, 30 minutes, 1, 2, 4, 8 hours, and 1, 2, 3, 4, 7 days. Plasma was collected from the blood by centrifugation and stored at -8O 0 C. The tissue at the injection site was also collected, homogenized in 5x methanol, and stored at -8O 0 C. Two samples were collected for each time point.
  • Plasma 200 ⁇ l was acidified with 10 ⁇ l of formic acid and precipitated with 600 ⁇ l of acetonitrile. The supernatant was collected by centrifugation and concentrated to dryness under vacuum. The residues were dissolved in 100 ⁇ l of 30% acetonitrile in water and centrifuged. 50 ⁇ l of the supernatant was injected for LC-MS/MS analysis. Tissue methanol extract (50 ⁇ l) was directly injected for LC-MS/MS analysis.
  • LC-MS/MS analysis was done with an API4000 mass spectrometer system equipped with a Turbo Ionspray probe.
  • the MRM mode of molecular ion detection was used with the ion pair of 835.5 and 136.1 for Example 2, and the ion pair of 858.5 and 136.1 for Example 3.
  • HPLC separation was performed with a Symmetry C4 2.1 x 50 mm 3.5 ⁇ column run from 30% B to 95% B in 10 minutes at a flow rate of 0.30 ml/minute.
  • Buffer A is 1% formic acid in water and buffer B is 1% formic acid in acetonitrile.
  • LOQ was 2.0 ng/ml for Example 2, and 1.0 ng/mL for Example 3.
  • the plasma concentrations of the peptide were calculated with its standard calibration curve. 0.18 mg/ml of Examples 2 and 3 (0.9 mg/rat in 5 ml methanol extract) was used as the 100% to calculate the percentages left at the injection sites. The results are listed in Table 6.
  • Example 2 The tissue accumulation profile of Example 2 at the injection site is shown in FIG. 2.
  • Example 3 The tissue accumulation profile of Example 3 at the injection site is shown in FIG. 4.
  • Some pharmacokinetic profiles of Examples 2 and 3 are shown in Table 7.
  • the results indicate that the peptides of GIP disclosed in the present application, particularly in combination with a divalent metal salt, provide for acceptable sustained release formulations.
  • the data also indicate that, after the subcutaneous injection, the GIP compound precipitated at the injection site and formed a depot. The GIP compound was then slowly released into the body fluid and the bloodstream.

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Abstract

La présente invention concerne des améliorations de compositions contenant un analogue de polypeptide insulinotrope glucose-dépendant ou ses sels pharmaceutiques et l'utilisation de ces compositions pour le traitement d'états médiés par le récepteur de GIP, comme le diabète sucré non-insulinodépendant et l'obésité. En particulier, la présente invention concerne une composition pharmaceutique d'une solution aqueuse limpide, ou d'un gel ou d'un semi-solide, comprenant le GIP natif, l'un de ses fragments, un analogue de GIP ou l'un de ses sels pharmaceutiquement acceptables (qui sont collectivement désignés par « peptide GIP » ou « composé GIP »), et un composant de métal divalent ou de sel de métal divalent comme ZnCl2 ou ZnAc2, la solution aqueuse limpide du peptide GIP précipitant in vivo à pH physiologique pour former un dépôt in situ qui est lentement dissous et libéré dans le fluide corporel et la circulation sanguine.
PCT/US2009/004545 2008-08-07 2009-08-07 Compositions pharmaceutiques d'analogues de polypeptide insulinotrope glucose-dépendant WO2010016936A1 (fr)

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WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012167744A1 (fr) * 2011-06-10 2012-12-13 Beijing Hanmi Pharmaceutical Co., Ltd. Analogues de polypeptides insulinotropes dépendants du glucose, compositions pharmaceutiques et son utilisation
EP2547351A1 (fr) * 2010-03-15 2013-01-23 Ipsen Pharma S.a.S. Compositions pharmaceutiques contenant des ligands de récepteurs sécrétagogues d'hormone de croissance
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
KR101390589B1 (ko) 2012-05-30 2014-04-30 가천대학교 산학협력단 다이아민을 포함하는 당뇨병의 예방 또는 치료용 조성물
US9023986B2 (en) 2010-10-25 2015-05-05 Hoffmann-La Roche Inc. Glucose-dependent insulinotropic peptide analogs
WO2016034186A1 (fr) * 2014-09-05 2016-03-10 University Of Copenhagen Analogues peptidiques de gip
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US10905772B2 (en) 2017-01-17 2021-02-02 Amgen Inc. Method of treating or ameliorating metabolic disorders using GLP-1 receptor agonists conjugated to antagonists for gastric inhibitory peptide receptor (GIPR)
WO2021110845A1 (fr) * 2019-12-03 2021-06-10 Antag Therapeutics Aps Analogues peptidiques de gip optimisés
WO2021193983A3 (fr) * 2020-03-25 2021-11-04 Takeda Pharmaceutical Company Limited Dosage d'une fois par semaine de composés peptidiques de l'agoniste du récepteur du gip et leurs utilisations
US11572399B2 (en) 2017-05-31 2023-02-07 University Of Copenhagen Long-acting GIP peptide analogues

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US9314509B2 (en) 2009-11-16 2016-04-19 Ipsen Pharma S.A.S. Pharmaceutical compositions of melanocortin receptor ligands
JP2013522301A (ja) * 2010-03-15 2013-06-13 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ 成長ホルモン分泌促進物質受容体リガンドの医薬組成物
EP2547351A1 (fr) * 2010-03-15 2013-01-23 Ipsen Pharma S.a.S. Compositions pharmaceutiques contenant des ligands de récepteurs sécrétagogues d'hormone de croissance
EP2547351A4 (fr) * 2010-03-15 2013-08-28 Ipsen Pharma Sas Compositions pharmaceutiques contenant des ligands de récepteurs sécrétagogues d'hormone de croissance
DE102010015123A1 (de) 2010-04-16 2011-10-20 Sanofi-Aventis Deutschland Gmbh Benzylamidische Diphenylazetidinone, diese Verbindungen enthaltende Arzneimittel und deren Verwendung
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
US9023986B2 (en) 2010-10-25 2015-05-05 Hoffmann-La Roche Inc. Glucose-dependent insulinotropic peptide analogs
KR20140043780A (ko) * 2011-06-10 2014-04-10 베이징 한미 파마슈티컬 컴퍼니 리미티드 포도당 의존성 인슐리노트로핀 폴리펩타이드 유사물질, 이의 약학적 조성물 및 응용
CN103764673A (zh) * 2011-06-10 2014-04-30 北京韩美药品有限公司 葡萄糖依赖性促胰岛素多肽类似物、其药物组合物及应用
WO2012167744A1 (fr) * 2011-06-10 2012-12-13 Beijing Hanmi Pharmaceutical Co., Ltd. Analogues de polypeptides insulinotropes dépendants du glucose, compositions pharmaceutiques et son utilisation
US9453062B2 (en) 2011-06-10 2016-09-27 Beijing Hanmi Pharmaceutical Co., Ltd. Glucose dependent insulinotropic polypeptide analogs, pharmaceutical compositions and use thereof
KR102002783B1 (ko) 2011-06-10 2019-07-24 베이징 한미 파마슈티컬 컴퍼니 리미티드 포도당 의존성 인슐리노트로핀 폴리펩타이드 유사물질, 이의 약학적 조성물 및 응용
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
EP2567959A1 (fr) 2011-09-12 2013-03-13 Sanofi Dérivés d'amide d'acide 6-(4-Hydroxy-phényl)-3-styryl-1H-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
KR101390589B1 (ko) 2012-05-30 2014-04-30 가천대학교 산학협력단 다이아민을 포함하는 당뇨병의 예방 또는 치료용 조성물
US10968266B2 (en) 2014-09-05 2021-04-06 University Of Copenhagen GIP peptide analogues
WO2016034186A1 (fr) * 2014-09-05 2016-03-10 University Of Copenhagen Analogues peptidiques de gip
US10294303B2 (en) 2015-12-23 2019-05-21 Amgen Inc. Method of treating or ameliorating metabolic disorders using binding proteins for gastric inhibitory peptide receptor (GIPR) in combination with GLP-1 agonists
US11046774B2 (en) 2015-12-23 2021-06-29 Amgen Inc. Method of treating or ameliorating metabolic disorders using binding proteins for gastric inhibitory peptide receptor (GIPR) in combination with GLP-1 agonists
US10905772B2 (en) 2017-01-17 2021-02-02 Amgen Inc. Method of treating or ameliorating metabolic disorders using GLP-1 receptor agonists conjugated to antagonists for gastric inhibitory peptide receptor (GIPR)
US11572399B2 (en) 2017-05-31 2023-02-07 University Of Copenhagen Long-acting GIP peptide analogues
WO2021110845A1 (fr) * 2019-12-03 2021-06-10 Antag Therapeutics Aps Analogues peptidiques de gip optimisés
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