Integrin Antagonists

Abstract

Provided herein are integrin antagonists and methods of using the same. For example, one or more of the compounds or polypeptides provided herein can be used in the treatment of disorders such as heart attacks, stroke, and cancer metastasis.

1 .- 181 . (canceled) 
     
     
         182 . A compound, or a pharmaceutically acceptable salt thereof, which is a pure antagonist of an integrin, wherein:
 the compound comprises the amino acid sequence RGD, wherein the RGD is substituted by at least one 5-12 membered heteroaryl group; and   upon contacting the compound and the integrin:   the compound stabilizes the integrin in an inactive state and exhibit a compound-integrin interaction selected from the group consisting of:   an interaction between the aromatic ring of Tyr122 and a cation;   an interaction between the aromatic ring and exposed adjacent methylene groups;   a hydrogen bond interaction with a residue corresponding to Tyr122 in the βA domain;   a salt bridge interaction with a residue corresponding to Lys125 in the βA domain; and   an interaction with a Mn 2+  or Ca 2+  ion at ADMIDAS through a water molecule;   or any combination thereof.   
     
     
         183 . The compound of  claim 182 , or a pharmaceutically acceptable salt thereof, wherein the compound comprises the sequence RGD, which is substituted by an indolyl group. 
     
     
         184 . The compound of  claim 182 , or a pharmaceutically acceptable salt thereof, wherein upon contacting the compound with a binding pocket of the integrin, the inhibits integrin activation. 
     
     
         185 . The compound of  claim 182 , or a pharmaceutically acceptable salt thereof, wherein upon contacting the compound with a binding pocket of the integrin, the 5-12 membered heteroaryl group inhibits integrin activation sterically. 
     
     
         186 . The compound of  claim 184 , or a pharmaceutically acceptable salt thereof, wherein the compound is about 14.5 ű1.5 Šin shape, and is of a size sufficient to interact with a binding pocket of the integrin. 
     
     
         187 . The compound of  claim 186 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pure antagonist of an αV integrin. 
     
     
         188 . The compound of  claim 186 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pure antagonist of αVβ3. 
     
     
         189 . The compound of  claim 184 , or a pharmaceutically acceptable salt thereof, wherein the compound is about 16.6 ű1.5 Šin shape, and is of a size sufficient to interact with a binding pocket of the integrin that is. 
     
     
         190 . The compound of  claim 189 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pure antagonist of an αII integrin. 
     
     
         191 . The compound of  claim 189 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pure antagonist of αIIbβ3. 
     
     
         192 . The compound of  claim 184 , or a pharmaceutically acceptable salt thereof, wherein the compound is about 10.5 ű1.5 Šin shape, and is of a size sufficient to interact with a binding pocket of the integrin that is. 
     
     
         193 . The compound of  claim 192 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pure antagonist of an α4 integrin. 
     
     
         194 . The compound of  claim 192 , or a pharmaceutically acceptable salt thereof, wherein the compound is a pure antagonist of α4β7. 
     
     
         195 . A pharmaceutical composition comprising a compound of  claim 182 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. 
     
     
         196 . A method of preventing platelet activation and aggregation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of  claim 182 , or a pharmaceutically acceptable salt thereof. 
     
     
         197 . A method of treating or preventing thrombosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of  claim 182 , or a pharmaceutically acceptable salt thereof. 
     
     
         198 . The method of  claim 197 , wherein the thrombosis is associated with activation of integrin.