ABSTRACT
Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC(50) of 2.4+/-0.6 nM, Akt cell potency of 50+/-19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Disease Models, Animal , Drug Design , Inhibitory Concentration 50 , Mice , Molecular Conformation , Molecular Structure , Pyrimidines/chemistry , Pyrroles/chemistry , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
