US2009208565A1PendingUtilityA1

Stabilized exendin-4 compounds

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Assignee: ZEALAND PHARMA ASPriority: Oct 2, 2002Filed: May 4, 2009Published: Aug 20, 2009
Est. expiryOct 2, 2022(expired)· nominal 20-yr term from priority
Inventors:Kirsten EbbehojTrine JepsenCarsten Boye KnudsenBjarne Due LarsenDavid Knott
A61P 9/10A61P 3/06A61P 3/04A61P 3/10A61P 3/00A61P 25/18C07K 14/57563A61K 38/00A61P 1/00C07K 14/575C07K 14/47C07K 14/46
56
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Claims

Abstract

The present invention discloses compositions comprising a stabilized Exendin-4 (1-39) and related compounds. The invention describes stabilized Exendin-4 agonists that include at least one modified amino acid residue particularly at positions Gln13, Met14, Trp25, or Asn28 of the Exendin-4 (1-39) molecule. Disclosed are preferred modifications of deaminated, hydrolyzed, oxidized, or isomerized reaction products of the specified amino acid residues corresponding to the same positions in the Exendin-4 (1-39) molecule. The invention also relates to methods of making and using the stabilized Exendin compounds, such as for the treatment of diabetes.

Claims

exact text as granted — not AI-modified
1 . A composition comprising an exendin-4 (1-39) analog which comprises at least one modification which is selected from the group consisting of:
 (i) an alpha-asparate (Asp) or beta-aspartate (isoaspartyl) or cyclic imide residue at a position corresponding to the Asn residue at position 28 of exendin-4;   (ii) an oxidized methionine residue at a position corresponding to position 14 of exendin-4;   (iii) an oxidized tryptophan residue at a position corresponding to position 25 of exendin-4; and   (iv) a deamidated or hydrolyzed Gln at a position corresponding to position 13 of exendin-4;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         2 . The composition of  claim 1 , wherein the exendin-4 analog further comprises at least one peptide sequence Z of 4-20 amino acid residues covalently bound to the stabilized exendin. 
     
     
         3 . The composition of  claim 1 , wherein the exendin-4 analog further comprises a deletion of 0 to 5 amino acids at positions corresponding to position 34-38 of exendin-4. 
     
     
         4 . The composition of  claim 1 , wherein the oxidized methionine residue is selected from the group consisting of a methioninyl sulfoxide or a methioninyl sulfone. 
     
     
         5 . The composition of  claim 1 , wherein the oxidized tryptophan residue comprises an oxidized 3H-indol-3-yl group. 
     
     
         6 . The composition of  claim 1 , wherein the oxidized tryptophan residue is selected from the group consisting of N-formylkynurenine (NFK), 3-hydroxykynurenine (3-OH-KYN), hydroxytryptophan (HTRP), and kynurenine (KYN). 
     
     
         7 . The composition of  claim 1 , wherein the cyclic imide residue is selected from the group consisting of an aspartimide and a glutimide. 
     
     
         8 . The composition of  claim 1 , wherein Z comprises between about 4 to about 20 Lys amino acid units. 
     
     
         9 . The composition of  claim 1 , wherein Z comprises 6 Lys amino acid units. 
     
     
         10 . The composition of  claim 1 , wherein Z is covalently bound to the stabilized exendin-4 (1-39) analog at the C-terminal carbonyl function. 
     
     
         11 . The composition of  claim 10  further comprising the following group linked to the C-terminus of the compound: -Lys 6 -NH 2  (SEQ ID NO:106). 
     
     
         12 . The composition of  claim 1 , wherein the stabilized exendin-4 (1-39) analog is selected from the group consisting of:
 des Pro 36 [Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:15),   des Pro 36 [IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:16),   des Pro 36 [Met(O) 14 ,Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:20),   des Pro 36 [Met(O) 14 ,IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:21),   des Pro 36 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:98),   des Pro 36 [Trp(O 2 ) 25 ,IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:99),   des Pro 36 [Met(O) 14  Trp(O 2 ) 25  Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:24),   des Pro 36 [Met(O) 14 ,Trp(O 2 ) 25 ,IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:25),   des Pro 36 [Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:17),   des Pro 36 [Met(O) 14 ,Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:22),   des Pro 36 [Met(O) 14 ,Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:26),   [Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:83),   [IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:84),   [Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:85),   [Glu 13 ,Asp 28 ]Exendin-4-NH 2  (SEQ ID NO:9),   [Met(O) 14 ,Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:88),   [Met(O) 14 ,IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:89),   [Met(O) 14 ,Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:90),   [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:92),   [Trp(O 2 ) 25 ,IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:93),   [Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:94),   [Met(O) 14  Trp(O 2 ) 25  Asp 28 ]Exendin-4 (1-39) (SEQ ID NO:95),   [Met(O) 14 ,Trp(O 2 ) 25 ,IsoAsp 28 ]Exendin-4 (1-39) (SEQ ID NO:96), and   [Met(O) 14 ,Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4 (1-39) (SEQ ID NO:97).   
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         13 . The composition of  claim 1 , wherein the stabilized exendin-4 (1-39) analog is selected from the group consisting of:
 H-(Lys) 6 -des Pro 36 [Asp 28 ]Exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:27),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:29),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:30),   des Pro 36 ,Pro 37 ,Pro 38 [Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:31),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:32),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 31 [Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:33),   H-(Lys) 6 -des Pro 36 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:41),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:43),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:44),   des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:45),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:46),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:47),   H-(Lys) 6 -des Pro 36 [Met(O) 14 ,Asp 28 ]Exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:55),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:57),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:58),   des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:59),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 , Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:60),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:61),   H-Lys 6 -des Pro 36 [Met(O) 14 ,Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:69),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:71),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:72),   des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 14 ,Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:73),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Met(O) 1 4 ,Trp(O 2 ) 25 ,Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:74),   H-Asn-(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 [Met(O) 14 , Trp(O 2 ) 25 , Asp 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:75),   H-(Lys) 6 -des Pro 36 [Cyclic imide 28 ]Exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:34),   des Pro 36 ,Pro 37 ,Pro 38 [Cyclic imide 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:35),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Cyclic imide 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:36),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Cyclic imide 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:37),   des Pro 36 ,Pro 37 ,Pro 38 [Cyclic imide 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:38),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Cyclic imide 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:39),   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Cyclic imide 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:40),   H-(Lys) 6 -des Pro 36 [Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:48),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:50),   H-Asn-(Glu) 5 -des Pro 3 ,Pro 7 ,Pro 38 [Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4(1-39)-NH 2  (SEQ ID NO:51),   des Pro 36 ,Pro 37  Pro 38 [Trp(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:52),   H-(Lys) 6 -des Pro 36 ,Pro 37 ,Pro 38 [Tip(O 2 ) 25 ,Cyclic imide 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:53), and   H-Asn-(Glu) 5 -des Pro 36 ,Pro 37 ,Pro 38 [Trp(O 2 ) 25 , Cyclic imide 28 ]Exendin-4(1-39)-(Lys) 6 -NH 2  (SEQ ID NO:54),   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         14 . The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
         15 . The composition of  claim 14 , wherein the composition comprises a depot formulation, microspheres, or liposomes or the composition includes a stabilized liquid formulation. 
     
     
         16 . A method of treating diabetes type 1 or type 2, insulin resistance syndrome, impaired glucose tolerance (IGT), obesity, eating disorders, hyperglycemia, metabolic disorders, and gastric disease, disease states associated with elevated blood glucose levels, regulation of blood glucose levels, regulation of gastric emptying, stimulating insulin release, the method comprising administering a therapeutically effective amount of the composition of  claim 1 .

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