Human G Protein-Coupled Receptor and Modulators Thereof for the Treatment of Atherosclerosis and Atherosclerotic Disease and for the Treatment of Conditions Related to MCP-1 Expression

Abstract

The present invention relates to methods of using a G protein-coupled receptor (GPCR) to identify whether a candidate compound is a modulator of atherogenesis. In certain embodiments, the GPCR couples to Gi. In certain embodiments, the GPCR is human. Agonists of the invention are useful as therapeutic agents for the prevention or treatment of atherosclerosis and atherosclerotic disease, including coronary artery disease, myocardial infarction, peripheral arterial disease, and ischemic stroke. Agonists of the invention are additionally useful as therapeutic agents for the prevention or treatment of conditions related to MCP-1 expression, including but not limited to rheumatoid arthritis, Crohn's disease, and multiple sclerosis.

1 - 57 . (canceled) 
     
     
         58 . A method comprising:
 (a) contacting a candidate compound with a G protein-coupled receptor (GPCR) comprising an amino acid sequence having at least 80% identity to SEQ ID NO:2, wherein said GPCR is present on a cell or isolated membrane thereof;   (b) determining the ability of the compound to inhibit or stimulate said GPCR; and   (c) determining if said compound modulates atherogenesis.   
     
     
         59 . The method of  claim 58 , wherein said determining element (c) comprises administering said compound to a mammal. 
     
     
         60 . The method of  claim 59 , wherein said determining element (b) comprises detecting stimulation of said GPCR and element (c) comprises detecting inhibition of atherogenesis. 
     
     
         61 . The method of  claim 59 , wherein said determining element (c) comprises determining if said compound treats or prevents atherosclerosis, coronary artery disease, myocardial infarction, peripheral artery disease or ischemic stroke. 
     
     
         62 . A compound that stimulates a G protein-coupled receptor comprising an amino acid having at least 80% identity to SEQ ID NO:2, wherein said compound is identified using the method of  claim 58 . 
     
     
         63 . A pharmaceutical composition comprising the compound of  claim 62  and a pharmaceutically acceptable carrier. 
     
     
         64 . The pharmaceutical composition of  claim 63 , further comprising a second pharmaceutically active agent. 
     
     
         65 . A method of treating or preventing an atherosclerotic disease, comprising administering the pharmaceutical composition of  claim 63  to a mammal having said atherosclerotic disease. 
     
     
         66 . A method comprising:
 (a) contacting a compound with a GPCR comprising an amino acid sequence having at least 80% identity to SEQ ID NO:2;   (b) determining the ability of the compound to bind to said GPCR; and   (c) determining if said compound modulates atherogenesis.   
     
     
         67 . The method of  claim 66 , wherein said determining element (c) comprises contacting said compound with a macrophage and determining if said compound modulates ATP-binding cassette transporter 1 (ABCA1) expression. 
     
     
         68 . The method of  claim 66 , wherein said determining element (c) comprises contacting said compound with a macrophage and determining if said compound modulates monocyte chemoattractant protein-1 (MCP-1) expression. 
     
     
         69 . The method of  claim 66 , wherein said determining element (c) comprises determining if said compound treats or prevents atherosclerosis, coronary artery disease, myocardial infarction, peripheral artery disease or ischemic stroke. 
     
     
         70 . The method of  claim 66 , wherein said method further comprises admixing said compound with a pharmaceutically acceptable carrier to produce a pharmaceutical composition. 
     
     
         71 . A method of treating or preventing an atherosclerotic disease, comprising administering the pharmaceutical composition of  claim 70  to a mammal having said atherosclerotic disease. 
     
     
         72 . A method of preparing a pharmaceutical composition, comprising admixing a compound that has been determined to modulate atherogenesis using the method of  claim 66  with a pharmaceutically acceptable carrier. 
     
     
         73 . A method comprising:
 (a) contacting a candidate compound with a GPCR comprising an amino acid sequence having at least 80% identity to SEQ ID NO:2, wherein said GPCR is present on a cell or isolated membrane thereof;   (b) determining the ability of the compound to inhibit or stimulate said GPCR; and   (c) determining if said compound modulates inflammation.   
     
     
         74 . A compound that stimulates a G protein-coupled receptor comprising an amino acid sequence having at least 80% identity to SEQ ID NO:2, wherein said compound is identified using the method of  claim 73 . 
     
     
         75 . A pharmaceutical composition comprising the compound of  claim 74  and a pharmaceutically acceptable carrier. 
     
     
         76 . A method of treating inflammation, comprising administering the pharmaceutical composition of  claim 75  to a mammal having inflammation. 
     
     
         77 . The method of  claim 73 , wherein said method further comprises admixing said compound with a pharmaceutically acceptable carrier to produce a pharmaceutical composition.