Conformationallly constrained peptidomimetics as β-turn templates and modulators of SH3 domains
AssigneeOSI Pharmaceuticals, Inc.
InventorsArlindo L. Castelhano, David J. Witter
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Abstract
Spirolactam compounds useful as inhibitors of protein-protein interactions modulated by SH3 domains are disclosed. Compounds of the invention are also useful as β-turn mimetics. Also disclosed are libraries of compounds of the invention, pharmaceutical compositions of the compounds of the invention, and methods for using the compounds of the invention to inhibit growth of a cell or to inhibit protein-protein interactions modulated by SH3 domains.
Claims24
A compound represented by the formula:
- in which
- R1 is alkyl, aryl, alkylcarbonyl, arylcarbonyl, aminocarbonyl,
- N-substituted carbonylamino, alkoxycarbonyl, aryloxycarbonyl, alkylsulforyl, arylsulfonyl, amino acyl;
- N-substituted aminoacyl, or a peptide group;
- R2 is alkyl, aryl, or —C(R2a)(R2b)C(O)R5;
- R2a and R2b are each independently alkyl, aryl;
- or a side-chain moiety of a naturally occurring amino acid other than glycine, or R2a and R2b, taken together with the carbon atom to which they are attached, form a 3 to 8 membered carbocyclic or heterocyclic ring;
- wherein the spirocyclic carbon atom is of the R configuration;
- R3 and R4 are each, independently for each occurrence, hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, cyano, or trifluoromethyl;
- R5 is hydroxy, alkyl, aryl, amino, alkoxy, aryloxy, —SH, alkylthio, peptide or arylthio;
- m and n are each independently 1 or 2;
- or a salt thereof.
A library of compounds represented by the formula (Formula 1):
- in which
- R1 is alkyl, aryl, alkylcarbonyl, arylcarbonyl, aminocarbonyl, N-substituted carbonylamino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, amino acyl, N-substituted aminoacyl, or a peptide group;
- R2 is alkyl, aryl, or —C(R2a)(R2b)C(O)R5;
- R2a and R2b are each independently alkyl, aryl or a side-chain moiety of a naturally occurring amino acid other than glycine;
- or
- R2a and R2b, taken together with the carbon atom to which they are attached, form a 3 to 8 membered carbocyclic or heterocyclic ring;
- wherein the spirocyclic carbon atom is of the R configuration;
- R3 and R4 are each, independently for each occurrence, hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, cyano, or trifluoromethyl;
- R5 is hydroxy, alkyl, aryl, amino, alkoxy, aryloxy, —SH, alkylthio, peptide or arylthio;
- m and n are each independently 1 or 2, or a salt thereof.
A method for inhibiting the binding of an SH3 binding signal transduction protein with an SH3 domain-containing protein comprising contacting the SH3 domain-containing protein with a compound represented by the formula (Formula I):
- in which
- R1 is alkyl, aryl, alkylcarbonyl, arylcarbonyl, aminocarbonyl, N-substituted carbonylamino, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, amino acyl , N-substituted aminoacyl, or a peptide group;
- R2 is alkyl, aryl, or —C(R2a) (R2b)C(O)R5;
- R2a and R2b are each independently hydrogen, alkyl, aryl or a side-chain moiety of a naturally occurring amino acid other than glycine, or R2a and R2b, taken together with the carbon atom to which they are attached, form a 3 to 8 membered carbocyclic or heterocyclic ring;
- wherein the spirocyclic carbon atom is of the R configuration;
- R3 and R4 are each, independently for each occurrence, hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, cyano, or trifluoromethyl;
- R5 is hydroxy, alkyl, aryl, amino, alkoxy, aryloxy, —SH, alkylthio, peptide or arylthio;
- m and n are each independently 1 or 2;
- or a salt thereof,
- such that the compound binds to the SH3 domain-containing protein.
Dependencies are inferred from the claim text.