Compounds and methods for the treatment of ocular disorders

Abstract

Described herein are compositions and methods for the treatment or prevention of ocular surface disorders including meibomian gland dysfunction, blepharitis, dry eye disease and other inflammatory and/or infectious diseases of the anterior surface of the eye(s). Said compositions and methods comprise keratolytic conjugates which demonstrate keratolytic activity, and anti-inflammatory or other desirable activities. Topical administration of said compositions to the eyelid margin or surrounding areas provides therapeutic benefit to patients suffering from ocular surface disorders.

1 . (canceled) 
     
     
         2 . A compound having a structure represented by Formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, 
         wherein,
 L is bond, —(C═O)(OCR 8 R 9 ) z —, or —(C═O)(CR 8 R 9 ) z O—;
 each R 8  and R 9  is independently H, halogen, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 3 -C 5 -cycloalkyl, or R 8  and R 9  are taken together with the atoms to which they are attached to form a C 3 -C 5 -cycloalkyl; 
 z is 1-6; 
 
 X is absent or —O—; and 
 R is substituted alkyl, 
 the substituted alkyl being substituted with one or more alkyl substituent, at least one alkyl substituent being independently selected from the group consisting of —SH, substituted or unsubstituted cycloalkyl, and substituted saturated heterocyclyl. 
 
       
     
     
         3 . The compound of  claim 1 , wherein R is alkyl substituted with —SH. 
     
     
         4 . The compound of  claim 1 , wherein R alkyl substituted with substituted or unsubstituted cycloalkyl. 
     
     
         5 . The compound of  claim 4 , wherein R alkyl substituted with substituted unsaturated cycloalkyl. 
     
     
         6 . The compound of  claim 1 , wherein R is alkyl substituted with substituted saturated heterocyclyl. 
     
     
         7 . The compound of  claim 6 , wherein the substituted saturated heterocyclyl is dithiolanyl oxide. 
     
     
         8 . The compound of  claim 1 , wherein X is absent. 
     
     
         9 . The compound of  claim 1 , wherein L is a bond. 
     
     
         10 . The compound of  claim 1 , wherein L is —(C═O)(OCR 8 R 9 ) z O—. 
     
     
         11 . The compound of  claim 10 , wherein each R 8  and R 9  is H. 
     
     
         12 . The compound of  claim 10 , wherein z is 1-4. 
     
     
         13 . The compound of  claim 1 , wherein X is absent and L is a bond. 
     
     
         14 . The compound of  claim 1 , wherein X is absent and L is —(C═O)(OCR 8 R 9 ) z O—. 
     
     
         15 . The compound of  claim 1 , wherein R is alkyl substituted with —SH, X is absent, and L is a bond. 
     
     
         16 . The compound of  claim 1 , wherein R is alkyl substituted with dithiolanyl oxide, X is absent, and L is a bond. 
     
     
         17 . The compound of  claim 1 , wherein R is alkyl substituted with dithiolanyl oxide, X is absent, and L is —(C═O)(OCR 8 R 9 ) z O—. 
     
     
         18 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the pharmaceutical composition is suitable for topical ophthalmic administration. 
     
     
         20 . A method of treating a dermal or an ocular disease or disorder in an individual, comprising administering to the individual a compound of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein the dermal or the ocular disease or disorder is associated with keratosis, microbial infiltration, microbial infection, inflammation, or any combination thereof.