GLP-1 receptor modulators
Compounds are provided that modulate the glucagon-like peptide 1 (GLP-1) receptor, as well as methods of their synthesis, and methods of their therapeutic and/or prophylactic use. Such compounds can act as modulators or potentiators of GLP-1 receptor on their own, or with incretin peptides such as GLP-1(7-36) and GLP-1(9-36), or with peptide-based therapies, such as exenatide and liraglutide, and have the following general structure (where “ ” represents either or both the R and S form of the compound): where A, B, C, Y 1 , Y 2 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , W 1 , n, p and q are as defined herein.
1. A method of treating type II diabetes, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a patient, comprising administering to the patient an effective amount of a compound having one of the following structures:
or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof, wherein
R 2 is —NR 41 R 42 ;
R 3 is alkyl, alkyl substituted with cyano, or —S(O 2 )(alkyl);
R 41 and R 42 taken together with the N atom to which they are attached form a 4-membered heterocyclyl substituted with —COOH; and
R 5 is cycloalkyl optionally substituted singly or multiply with halo, alkyl or haloalkyl.
2. The method of claim 1 wherein the malcondition is type II diabetes.
3. The method of claim 1 wherein the malcondition is non-alcoholic fatty liver disease.
4. The method of claim 1 wherein the malcondition is non-alcoholic steatohepatitis.
5. The method of claim 1 , wherein R 41 and R 42 taken together with the N atom to which they are attached form a 4-membered heterocyclyl having the following structure:
6. The method of claim 1 , wherein 4-membered heterocyclyl is substituted with —COOH to provide the following structure:
7. The method of claim 1 , wherein R 3 is ethyl, iso-propyl, cyclopropyl, iso-butyl or tert-butyl.
8. The method of claim 1 , wherein R 3 is ethyl, iso-propyl, cyclopropyl, iso-butyl or tert-butyl, each of which is substituted with cyano.
9. The method of claim 1 , wherein R 3 is —SO 2 CH 3 .
10. The method of claim 1 , wherein R 5 is cyclohexyl singly or multiply substituted with halo, alkyl or haloalkyl.
11. The method of claim 1 , wherein R 5 is cyclohexyl singly substituted with alkyl.
12. The method of claim 1 , wherein R 5 is cyclohexyl singly substituted with methyl, ethyl, n-propyl, iso-propyl or tert-butyl.
13. The method of claim 1 , wherein R 5 is cyclohexyl singly or multiply substituted with halo or haloalkyl.
14. The method of claim 1 , wherein the compound has the structure of any one of the following compounds, or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof