L-pag derivatives for treatment of sleep disordered breathing (sdb)

Abstract

Described herein are novel γ- and δ-propargyl carboxylic acids and esters. The novel compositions are antagonists of CSE and may be used to modulate of the activity of the carotid body, therefore providing therapeutic benefits for sleep-related breathing disorders and related conditions.

1 - 112 . (canceled) 
     
     
         113 . A method of treating, preventing, or reducing a sleep-related breathing disorder in an individual in need thereof comprising administering a therapeutically effective amount of a cystathionine-γ-lyase (CSE) antagonist, wherein the CSE antagonist is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 3  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heterocycle; 
 R 4  and R 5  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or join to form a 3- to 6-membered substituted or unsubstituted cycloalkyl or heterocycle; and 
 A and B are each independently O, NH, SO 2 , or CH 2 ; 
 
       or a pharmaceutically acceptable salt, enantiomer, diastereomer, or prodrug thereof. 
     
     
         114 . The method of  claim 113 , wherein R 1  is hydrogen. 
     
     
         115 . The method of  claim 113 , wherein R 3  is hydrogen. 
     
     
         116 . The method of  claim 113 , wherein A is NH and B is SO 2 . 
     
     
         117 . The method of  claim 113 , wherein R 4  and R 5  are each methyl or phenyl. 
     
     
         118 . The method of  claim 113 , wherein R 4  and R 5  together form a cyclopentyl ring. 
     
     
         119 . The method of  claim 113 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         120 . The method of  claim 113 , wherein the CSE antagonist reduces CSE-catalyzed synthesis of hydrogen sulfide (H 2 S). 
     
     
         121 . The method of  claim 120 , wherein reduced synthesis of H 2 S results in attenuation of carotid body activity. 
     
     
         122 . The method of  claim 113 , wherein the CSE antagonist reduces chemosensitivity of the carotid body. 
     
     
         123 . The method of  claim 122 , wherein reduced carotid body chemosensitivity is reduction of arterial blood oxygen sensitivity. 
     
     
         124 . The method of  claim 122 , wherein reduced carotid body reduction chemosensitivity is reduction of arterial blood carbon dioxide sensitivity. 
     
     
         125 . The method of  claims 123 , wherein the reduced carotid body chemosensitivity reduces loop gain of the ventilator drive control system, blunts hypoventilation, lowers blood pressure, and/or dampens carotid sinus nerve activity. 
     
     
         126 . The method of  claim 113 , wherein the individual is suffering from or suspected to be suffering from a sleep-related breathing disorder selected from central sleep apnea (CSA), Cheyne-Stokes breathing-central sleep apnea (CSB-CSA), obesity hypoventilation syndrome (OHS), congenital central hypoventilation syndrome (CCHS), obstructive sleep apnea (OSA), idiopathic central sleep apnea (ICSA), narcotic-induced CSA, high altitude periodic breathing, chronic mountain sickness, impaired respiratory motor control associated with stroke, upper airway resistance syndrome (UARS), or impaired respiratory motor control associated with a neurologic disorder. 
     
     
         127 . The method of  claim 113 , further comprising administering a second therapeutic selected from carbonic anhydrase inhibitors, cholinesterase inhibitors, adenosine inhibitors, progestational agents, opioid antagonists, central nervous system stimulants, selective serotonin reuptake inhibitors (SSRis), antidepressants, antihypertensives, calcium channel antagonists, ACE inhibitors, respiratory stimulants, alpha-2 adrenergic agonists, gamma aminobutyric acid agonists, and glutamate antagonists. 
     
     
         128 . The method of  claim 113 , further comprising administering an additional therapeutic selected from acetazolamide, theophylline, progesterone, donepezil, naloxone, nicotine, paroxetine, protriptyline, metoprolol, cilazapril, propranolol, atenolol, hydrochlorothiazide, isradipine, spirapril, doxapram, clonidine, baclofen, and sabeluzole. 
     
     
         129 . The method of  claim 113 , wherein the CSE antagonist is administered orally, subcutaneously, topically, intramuscularly, or intravenously. 
     
     
         130 . The method of  claims 124 , wherein the reduced carotid body chemosensitivity reduces loop gain of the ventilator drive control system, blunts hypoventilation, lowers blood pressure, and/or dampens carotid sinus nerve activity.