Cystathionine-gamma-lyase (cse) inhibitors

Abstract

Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit cystathionine-γ-lyase (CSE). Also described herein are methods for using such CSE inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from CSE inhibition.

What is claimed is: 
     
         1 . A compound of Formula (I) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is a carboxylic acid isostere; 
 R 1  is substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
 
     
     
         2 . A compound of Formula (II) having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         A is selected from 
       
       
         
           
           
               
               
           
         
       
       or
 a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
 
     
     
         3 . The compound of  claim 2  wherein A is selected from 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound of Formula (III) having the structure: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         A is a carboxylic acid isostere selected from —SO 3 H, —SO 2 NHR 4 , —P(O)(OR 4 ) 2 , —P(O)(R 4 )(OR 4 ), —CON(R 4 ) 2 , —CONHNHSO 2 R 4 , —CONHSO 2 R 4 , —C(R 4 ) 2 B(OR 5 ) 2 , and —CON(R 4 )C(R 4 ) 2 B(OR 5 ) 2 ; wherein each R 4  is independently H, OH, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; and R 5  is H or C 1 -C 6 alkyl; or 
         a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         5 . The compound of any one of  claims 2 - 4  wherein R 1  is H, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. 
     
     
         6 . The compound of  claim 5  wherein R 1  is H. 
     
     
         7 . The compound of  claim 5  wherein R 1  substituted or unsubstituted C 1 -C 4 alkyl. 
     
     
         8 . The compound of  claim 7  wherein R 1  is —CH 3 . 
     
     
         9 . The compound of  claim 7  wherein R 1  is —CH 2 CH 3 . 
     
     
         10 . A compound of Formula (IV) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is 
 
       
         
           
           
               
               
           
         
         R 1  is substituted or unsubstituted C 2 -C 6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         11 . The compound of  claim 10  wherein R 1  is H, substituted or unsubstituted C 2 -C 6 alkyl, or substituted or unsubstituted heteroalkyl. 
     
     
         12 . The compound of  claim 11  wherein R 1  is H. 
     
     
         13 . The compound of  claim 11  wherein R 1  substituted or unsubstituted C 2 -C 6 alkyl. 
     
     
         14 . The compound of  claim 13  wherein R 1  is —CH 2 CH 3 . 
     
     
         15 . A compound of Formula (V) having the structure: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is 
 
       
         
           
           
               
               
           
         
         R 1  is H, substituted or unsubstituted C 3 -C 6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         16 . The compound of  claim 15  wherein R 1  is H, substituted or unsubstituted C 3 -C 6 alkyl, or substituted or unsubstituted heteroalkyl. 
     
     
         17 . The compound of  claim 16  wherein R 1  is H. 
     
     
         18 . The compound of  claim 16  wherein R 1  substituted or unsubstituted C 3 -C 6 alkyl. 
     
     
         19 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of  claims 1 - 18  or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. 
     
     
         20 . A method for treating or preventing or reducing the incidence of acute kidney injury (AKI) secondary to a toxic agent (e.g., cisplatin, aminoglycosides, and radiologic contrast material), nociceptive pain, acute post-operative pain, neuropathic pain, trigeminal neuralgia, diabetic peripheral neuropathy, herpetic neuralgia, post-herpetic neuralgia, inflammatory pain, mixed neuropathic pain and inflammatory pain states, rheumatoid arthritis, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, acute pancreatitis, chronic pancreatitis, pain associated with acute pancreatitis, pain associated with chronic pancreatitis, migraine headache, gout, ankylosing spondylititis, systemic lupus erythematosus (SLE), system inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome (MODS), asthma, chronic obstructive pulmonary disease (COPD), sensitive skin, acne, rosacea, contact dermatitis, or pain associated with cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of  claims 1 - 18  or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof. 
     
     
         21 . The method of  claim 20  for treating or preventing or reducing the incidence of acute post-operative pain, neuropathic pain, trigeminal neuralgia, diabetic peripheral neuropathy, herpetic neuralgia, post-herpetic neuralgia, inflammatory pain, rheumatoid arthritis, osteoarthritis, or migraine headache, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of  claims 1 - 20  or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable prodrug thereof 
     
     
         22 . The method of  claim 20  or  21 , further comprising administration of a second agent selected from carbonic anhydrase inhibitors, cholinesterase inhibitors, adenosine inhibitors, progestational agents, opiod antagonists, central nervous system stimulants, selective serotonin reuptake inhibitors (SSRIs), dual 5-HT-NE reuptake inhibitors (SNRI's), antidepressants, antihypertensives, calcium channel antagonists, ACE inhibitors, respiratory stimulants, alpha-2 adrenergic agonists, gamma aminobutyric acid agonists, antiepileptic drugs, NSAIDs, steroids, and glutamate antagonists. 
     
     
         23 . The method of  claim 20  or  21 , further comprising administration of a second agent selected from acetazolamide, theophylline, progesterone, donepezil, naloxone, nicotine, paroxetine, protriptyline, metoprolol, cilazapril, propranolol, atenolol, hydrochlorothiazide, isradipine, spirapril, doxapram, clonidine, baclofen, sabeluzole, gabapentin, pregablin, and duloxetine.