Patent ID: 6025147
Filing Date: 2000-02-15
Classification: A61K,A61P,C07K

Abstract:
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 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, wherein the chemical structure comprising at least two hydrogen bonding moieties is selected from the group consisting of: ##STR80## wherein. each X is independently C or N;each Z is CO or SO.sub.2 ;W.sub.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.sub.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,W.sub.14 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 C atoms through bonds r;W.sub.1a 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.sub.2a is a straight chain comprising 3-4 covalently bound members independently selected from the group consisting of C, N, S and O, said chain comprising two ends which are covalently bound to two different atoms to form an aryl or heteroaromatic ring therewith;each X.sub.1 is independently C, N, or O;W.sub.14a 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 saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X.sub.1 atoms to form a non-aromatic ring therewith;W.sub.3 is a straight chain comprising 24 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.sub.15 is a straight chain comprising 1-2 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;W.sub.16 is a straight chain comprising 1-2 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 C atoms through bonds r;W.sub.4 is a straight chain comprising 2-4 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 atoms,each W.sub.5 is a direct bond or a straight chain comprising 1-2 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 atoms through bonds r,W.sub.6 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 W.sub.17 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 C atoms through bonds r;W.sub.7 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;W.sub.8 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.sub.18 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 C atoms through bonds r;each W.sub.8a 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 C atoms,W.sub.19 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 C atoms through bonds r;W.sub.7a is a straight chain comprising 3 covalently bound members independently selected from the group consisting of C, N, S and O, said chain comprising two ends which are covalently bound to two different C atoms to form an aryl ring therewith;W.sub.9 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.sub.10 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.sub.9a 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 C atoms;W.sub.10a 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; andW.sub.11 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 atoms to form a ring which may optionally be benzofused or pyridinofused;W.sub.12 is a straight chain comprising 4-6 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 the indicated X atom through bonds r;each X.sub.b is independently C or N;W.sub.12a is a straight chain comprising 4-6 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 the indicated X.sub.b atom through bonds r; andW.sub.20 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 C atoms through bonds r;W.sub.21 is a straight chain comprising 1-2 covalently bound members independently selected from the group consisting of C, N, S and O, said chain comprising two ends which are covalently bound to two different C atoms to form an aryl ring therewith;W.sub.13 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 atoms,W.sub.22 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 atoms;W.sub.23 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 atoms; andW.sub.22a 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 atoms through bonds r;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 amide --NH-- groups or the carbonyl-C(=O)-groups 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; andf) accepting or rejecting said candidate compound as an ICE inhibitor based on the determinations and evaluations carried out in steps a) through e);wherein:1) one of said hydrophobic moieties associates with the P2 binding pocket of ICE, in such a way that:i) the distance from the center of mass of the hydrophobic moiety in the P2 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 7.1 .ANG. and about 12.5 .ANG.;ii) the distance from the center of mass of the hydrophobic moiety in the P2 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 6.0 .ANG. and about 12 .ANG.; andiii) the distance from the center of mass of the hydrophobic moiety in the P2 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 3.7 .ANG. and about 9.5 .ANG.;2) one of said hydrophobic moieties associates with the P3 binding pocket of ICE in such a way that:i) the distance from the center of mass of the hydrophobic moiety in the P3 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 3.9 .ANG. and about 9.5 .ANG.;ii) the distance from the center of mass of the hydrophobic moiety in the P3 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 4 .ANG. and about 13 .ANG.; andiii) the distance from the center of mass of the hydrophobic moiety in the P3 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 7.0 .ANG. and about 13 .ANG.;3) one of said hydrophobic moieties associates with the P4 binding pocket of ICE in such a way that:i) the distance from the center of mass of the hydrophobic moiety in the P4 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 4.5 .ANG. and about 7.5 .ANG.;ii) the distance from the center of mass of the hydrophobic moiety in the P4 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 5.5 .ANG. and about 8.5 .ANG.; andiii) the distance from the center of mass of the hydrophobic moiety in the P4 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 8 .ANG. and about 11 .ANG.; and4) one of said hydrophobic moieties associates with the P' binding pocket of ICE in such a way that:i) the distance from the center of mass of the hydrophobic moiety in the P' binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 11 .ANG. and about 16 .ANG.;ii) the distance from the center of mass of the hydrophobic moiety in the P' binding pocket to the amide nitrogen of Arg-341 of ICE is between about 10 .ANG. and about 15 .ANG.; andiii) the distance from the center of mass of the hydrophobic moiety in the P' binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 8 .ANG. and about 12 .ANG..