Vidyadhar M. Paradkar

Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors.

A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.

Novel pyrrolidine heterocycles as CCR1 antagonists

A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.

A regioselective synthesis of 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046), a potent phenylethanolamine N-methyltransferase inhibitor

Abstract A regioselective synthesis of 2,3,4,5-tetrahydro-1 H -2-benzazepines substituted on the aryl and/or azepine rings is presented and used for the preparation of the title compound in overall yield of 22% from intermediate 1 .