Inhibitors of store operated calcium release

Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases, disorders or conditions that would benefit from inhibition of SOC channel activity.

1 . A method of modulating store-operated calcium (SOC) channel activity comprising contacting the store-operated calcium (SOC) channel complex, or portion thereof, with a compound of Formula (I)-(XV) or Group A; or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof, described herein. 
     
     
         2 . The method of  claim 1  wherein the compound of Formula (I)-(XV) or Group A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 1 , wherein contacting occurs in vitro. 
     
     
         4 . The method of  claim 1 , wherein contacting occurs in vivo. 
     
     
         5 . The method of  claim 1 , wherein the compound of Formula (I)-(XV) or Group A modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of the store operated calcium channel complex selected from stromal interaction molecules (STIM) family of proteins. 
     
     
         6 . The method of  claim 5 , wherein the compound of Formula (I)-(XV) or Group A modulates an activity of, modulates an interaction of, or modulates the level of, or binds to, or interacts with at least one portion of STIM1 or STIM2. 
     
     
         7 . The method of  claim 1 , wherein modulating store operated calcium channel activity with a compound of Formula (I)-(XV) or Group A inhibits store-operated calcium entry (SOCE). 
     
     
         8 . The method of  claim 1 , wherein the store operated calcium channel complex is calcium-release activated calcium (CRAC) channel complex. 
     
     
         9 . The method of  claim 8 , wherein modulating calcium release activated calcium (CRAC) activity with a compound of Formula (I)-(XV) or Group A inhibits the electrophysiological current (I CRAC ) associated with activated CRAC channels. 
     
     
         10 . A method of treating a disease, disorder or condition in a mammal that would benefit from inhibition of store operated calcium channel activity comprising administering to the mammal a compound of Formula (I)-(XV) or Group A; or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof. 
     
     
         11 . The method of  claim 10 , wherein the compound of Formula (I)-(XV) or Group A modulates the activity of, modulates an interaction of, or binds to, or interacts with a mammalian STIM1 protein, or a mammalian STIM2 protein. 
     
     
         12 . The method of  claim 10 , wherein the disease, disorder or condition in a mammal is selected from diseases/disorders involving inflammation, glomerulonephritis, uveitis, hepatic diseases or disorders, renal diseases or disorders, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, organ transplant rejection, allogeneic or xenogeneic transplantation, graft rejection, graft-versus-host disease, lupus erythematosus, type I diabetes, pulmonary fibrosis, dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolytic anemia, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis, asthma, psoriasis, multiple sclerosis, Sjogren's syndrome, and autoimmune diseases or disorders. 
     
     
         13 . The method of  claim 12  wherein the disease, disorder, or condition is rheumatoid arthritis. 
     
     
         14 . The method of  claim 12  wherein the disease, disorder, or condition is psoriasis. 
     
     
         15 . The method of  claim 12  wherein the disease, disorder, or condition is multiple sclerosis. 
     
     
         16 . The method of  claim 12  wherein the disease, disorder, or condition is organ transplant rejection. 
     
     
         17 . The method of  claim 12  wherein the disease, disorder or condition is inflammatory bowel disease. 
     
     
         18 . The method of  claim 17  wherein inflammatory bowel disease is ulcerative colitis. 
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound of  claim 1  or pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.