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N-TERMINALLY MODIFIED GLP-1 RECEPTOR MODULATORS

  • US 20080045461A1
  • Filed: 05/25/2007
  • Published: 02/21/2008
  • Est. Priority Date: 05/26/2006
  • Status: Active Grant
First Claim
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1. An isolated polypeptide comprising a sequence of Formula I:


  • Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11+TMFormula I wherein, Xaa1 is a naturally or nonnaturally occurring amino acid comprising an imidazole or thiazole ring, such as histidine or thiazolylalanine;

    wherein any of the carbon atoms of said amino acid are optionally substituted with hydrogen with one or more alkyl groups, or with one or more halo groups;

    wherein the free amino group of said amino acid may be replaced with a hydroxyl or alkoxy group or is optionally substituted with, alkyl, acyl, benzoyl, alkyloxycarbonyl, methyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heterocyclyloxycarbonyl, heteroarylalkyloxycarbonyl, alkylcarbamoyl, arylcarbamoyl, aralkylcarbamoyl, heterocyclylsulfonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylalkylsulfonyl or heteroarylsulfonyl;

    and wherein the amino group of Xaa1 is optionally absent, such that Xaa1 is des-amino acid of histidine or thiazolylalanine in which any of the carbon atoms are optionally substituted with alkyl, halo, or hydroxyl groups;

    Xaa2 is naturally or nonnaturally occurring amino acid selected from the group consisting of α

    -amino-isobutyric acid (Aib);

    (L)-alanine, D-Alanine, N-methyl-L-Alanine, N-methyl-D-Alanine, (L)-proline, (S)-α

    -methyl-proline [α

    -Me-Pro], (L)-azetidine (Azt), (S)-α

    -methyl-azetidine (α

    -Me-Azt), (L)-valine, and (R)- or (S)-isovaline, and wherein the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;

    Xaa3 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example aspartic acid or glutamic acid; and

    wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;

    Xaa4 is glycine;

    Xaa5 is a naturally or nonnaturally occurring amino acid selected from the group consisting of (L)-threonine, (L)-allo-threonine, (L)-serine, (L)-norvaline, (L)-norleucine; and

    wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups or halo groups;

    Xaa6 is a naturally or nonnaturally occurring amino acid comprising an alpha carbon which is disubstituted;

    wherein one of the side chains of said amino acid contains an aromatic or heteroaromatic ring, for example alpha-methyl-phenylalanine, alpha-methyl-2-fluorophenylalanine, and alpha-methyl-2,6-difluorophenylalanine, wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl groups; and

    wherein any of the carbon atoms of said amino acid are optionally substituted with one or more halo groups;

    Xaa7 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which is substituted with a hydroxyl group, for example L-threonine or L-allo-threonine;

    wherein any of the carbon atoms of said amino acid are optionally substituted with one or more alkyl or halo groups;

    Xaa8 is a naturally or nonnaturally occurring amino acid selected from the group consisting of L-serine, L-histidine and L-asparagine;

    wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl groups or halo groups;

    Xaa9 is a naturally or nonnaturally occurring amino acid comprising an amino acid side chain which contains a carboxylic acid, for example L-aspartic acid or L-glutamic acid;

    wherein one or more of the carbon atoms of said amino acid is optionally substituted with one or more alkyl or halo groups;

    Xaa10 is a naturally or nonnaturally occurring amino acid of Formula II, III, or IV;

    wherein R3, R4 and R6 are each selected from the group consisting of hydrogen, alkyl, methyl, ethyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxyalkyl, cyano, amino, aminoalkyl, carboxyl, carboxyalkyl, alkoxy, methoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, and aryl sulfonyl;

    and wherein X1, X2, X3, X4, and X5 are each C or N, with the proviso that at least one of X1, X2, X3, X4, and X5 is N;

    Xaa11 is a naturally or nonnaturally occurring amino acid of Formula IIa, IIIa, or IVa;

    wherein the C-terminal carbonyl carbon of said amino acid is attached to a nitrogen to form a carboxamide (NH2), an alkyl carboxamide (NHR1), or a dialkylcarboxamide (NR1R2);

    wherein each of R1 and R2 is an alkyl or arylalkyl group;

    wherein R3a, R4a and R6a are each selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, heteroaryl, halogen, hydroxyl, hydroxyalkyl, cyano, amino, aminoalkyl, carboxyl, carboxyalkyl, alkoxy, methoxy, aryloxy, carboxamide, substituted carboxamide, alkyl ester, aryl ester, alkyl sulfonyl, and aryl sulfonyl;

    wherein R7 is selected from the group consisting of hydrogen, methyl, and ethyl;

    wherein X1, X2, X3, X4, and X5 are each C or N, with the proviso that at least one of X1, X2, X3, X4, and X5 is N; and

    wherein Xaa11 is not an amino acid of Formula IIa when Xaa10 is an amino acid of Formula II.

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