Method of modulating stress-activated protein kinase system

Abstract

Disclosed are methods of modulating a stress activated protein kinase (SAPK) system with an active compound, wherein the active compound exhibits low potency for inhibition of at least one p38 MAPK; and wherein the contacting is conducted at a SAPK-modulating concentration that is at a low percentage inhibitory concentration for inhibition of the at least one p38 MAPK by the compound. Also disclosed are derivatives of pirfenidone. These derivatives can modulate a stress activated protein kinase (SAPK) system.

1 .- 92 . (canceled) 
     
     
         93 . A method of modulating a stress activated protein kinase (SAPK) system, comprising contacting a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof; with a p38 mitogen-activated protein kinase (MAPK). 
     
     
         94 . A method of treating or preventing an inflammatory or fibrotic condition comprising
 administering to a subject in need thereof a effective amount of at least one compound selected from the group consisting of   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof; wherein the effective amount produces a blood or serum or other bodily fluid concentration that is less than an EC 30  for inhibition for at least one p38 MAPK. 
     
     
         95 . The method of  claim 94 , wherein the anti-inflammatory or fibrotic condition is selected from the group consisting of fibrosis, chronic obstructive pulmonary disease, inflammatory pulmonary fibrosis, idiopathic pulmonary fibrosis, bronchiolitis obliterans syndrome, chronic allograft fibrosis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, sepsis, septic shock; endotoxic shock, gram-negative sepsis, toxic shock syndrome, myofacial pain syndrome (MPS), Shigellosis, asthma, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, psoriasis, eczema, ulcerative colitis, glomerular nephritis, scleroderma, chronic thyroiditis, Grave's disease, Ormond's disease, autoimmune gastritis, myasthenia gravis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, pancreatic fibrosis, chronic active hepatitis, hepatic fibrosis, renal disease, renal fibrosis, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neural trauma, Alzheimer's disease, Huntington's disease, Parkinson's disease, acute or chronic pain, an allergy, cardiac hypertrophy, chronic heart failure, acute coronary syndrome, cachexia, malaria, leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acute synoviitis, muscle degeneration, bursitis, tendonitis, tenosynoviitis, herniated, ruptured, or prolapsed intervertebral disk syndrome, osteopetrosis, thrombosis, silicosis, pulmonary sarcosis, bone resorption disease, cancer, Multiple Sclerosis, lupus, fibromyalgia, AIDS, Herpes Zoster, Herpes Simplex, influenza virus, Severe Acute Respiratory Syndrome (SARS), cytomegalovirus, and diabetes mellitus. 
     
     
         96 . The method of  claim 94 , wherein the effective amount is less than 50% of an amount that causes an undesirable side effect in the subject. 
     
     
         97 . The method of  claim 94 , wherein the compound inhibits a kinase in the SAPK signaling pathway. 
     
     
         98 . The method of  claim 94 , wherein the administering of the compound is on a schedule selected from the group consisting of twice a day, once a day, once every two days, three times a week, twice a week, and once a week. 
     
     
         99 . The method of  claim 95 , wherein the administering of the compound is on a schedule selected from the group consisting of twice a day, once a day, once every two days, three times a week, twice a week, and once a week. 
     
     
         100 . The method of  claim 95 , wherein the anti-inflammatory or fibrotic condition is bronchiolitis. 
     
     
         101 . The method of  claim 95 , wherein the anti-inflammatory or fibrotic condition is chronic allograft fibrosis. 
     
     
         102 . The method of  claim 95 , wherein the anti-inflammatory or fibrotic condition is idiopathic pulmonary fibrosis. 
     
     
         103 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         104 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         105 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         106 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         107 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         108 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         109 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         110 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         111 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         112 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         113 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         114 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         115 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         116 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         117 . The method of  claim 94 , wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         118 . A method of identifying a pharmaceutically active compound, comprising:
 assaying a plurality of compounds from a library of compounds for inhibition of at least one p38 MAPK; and   selecting at least one compound from the plurality of compounds,   
       wherein the selected compound exhibits an EC 50  in the range of about 1 μM to about 1000 μM for inhibition of the at least one p38 MAPK. 
     
     
         119 . A method of identifying a pharmaceutically active compound, comprising:
 assaying a plurality of compounds from a library of compounds for inhibition of TNFα secretion in a bodily fluid in vivo; and   selecting at least one compound from the plurality of compounds, wherein the selected compound exhibits an EC 50  in the range of about 1 μM to about 1000 μM for inhibition of TNFα secretion in a bodily fluid in vivo.   
     
     
         120 . A compound having the formula of Subgenus III: 
       
         
           
           
               
               
           
         
       
       wherein
 X 3  is selected from the group consisting of H, F, and OH; 
 R 2  is selected from the group consisting of H and CF 3 ; and 
 wherein the compound exhibits an EC 50  in the range of about 1 μM to about 1000 μM for inhibition of p38 MAPK; or a pharmaceutically acceptable salt, ester, solvate or prodrug of the compound. 
 
     
     
         121 . A compound having the formula of Genus VII: 
       
         
           
           
               
               
           
         
         wherein X 3  is H, halogen, alkoxy, or OH; Y 1 , Y 2 , Y 3 , and Y 4  are independently selected from the group consisting of H, C 1 -C 10  alkyl, substituted C 1 -C 10  alkyl, C 1 -C 10  alkenyl, C 1 -C 10  haloalkyl, C 1 -C 10  nitroalkyl, C 1 -C 10  thioalkyl, C 1 -C 10  hydroxyalkyl, C 1 -C 10  alkoxy, phenyl, substituted phenyl, halogen, hydroxyl, C 1 -C 10  alkoxyalkyl, C 1 -C 10  carboxy, C 1 -C 10  alkoxycarbonyl; R 4  is H, halogen, or OH; and 
         wherein the compound exhibits an EC 50  in the range of about 1 μM to about 1000 μM for inhibition of p38 MAPK; or a pharmaceutically acceptable salt, ester, solvate or prodrug of the compound.