Inhibitors of interleukin-1 beta converting enzyme

Abstract

The present invention relates to novel classes of compounds which are inhibitors of interleukin-1β converting enzyme. The ICE inhibitors of this invention are characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting ICE activity and consequently, may be advantageously used as agents against interleukin-1 mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases. This invention also relates to methods for inhibiting ICE activity and methods for treating interleukin-1 mediated diseases using the compounds and compositions of this invention.

1 - 18 . (canceled) 
     
     
         19 . An ICE inhibitor comprising:
 (a) a scaffold of formula I:   
       
         
           
           
               
               
           
         
         wherein:
 each X is independently C or N; 
 Z is CO or SO 2 ; 
 W 1  is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r; 
 W 2  is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r; 
 each bond labeled r is independently a single or a double bond; 
 H is a first hydrogen bonding moiety and Z is a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide —NH— group of Arg-341, the carbonyl oxygen of Ser-339 and the amide —NH— group of Ser-339; 
 
         (b) a first and a second moderately hydrophobic moiety, said moieties each being covalently bound to said scaffold and each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P′ binding pocket; and 
         (c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being covalently bound to said scaffold and being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE. 
       
     
     
         20 - 76 . (canceled) 
     
     
         77 . A method for selecting an ICE inhibitor comprising the steps of:
 (a) selecting a candidate compound of defined chemical structure comprising at least two hydrogen bonding moieties, at least two moderately hydrophobic moieties and one electronegative moiety comprising one or more electronegative atoms attached either to the same atom or to adjacent atoms in the electronegative moiety;   (b) determining a low-energy conformation for binding of said compound to the active site of ICE;   (c) evaluating the capability of said compound in said conformation to form at least two hydrogen bonds with the non-carbon backbone atoms of Arg-341 and Ser-339 of ICE;   (d) evaluating the capability of said compound in said conformation to associate with at least two of the binding pockets of ICE selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P′ binding pocket;   (e) evaluating the capability of said compound in said conformation to interact with the P1 binding pocket of ICE; and   (f) accepting or rejecting said candidate compound as an ICE inhibitor based on the determinations and evaluations carried out in the preceeding steps.   
     
     
         78 . The method of  claim 77 , additionally comprising the following steps which follow step e) and precede step f):
 (g) evaluating the deformation energy of binding of said compound to ICE; and   (h) evaluating the contribution of the sum of all electrostatic interactions between said compound and ICE when said compound is bound thereto in said conformation.   
     
     
         79 . An ICE inhibitor selected by either of the methods according to  claim 77  or  78 . 
     
     
         80 - 124 . (canceled)