Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X(3) receptor antagonist.
Bioorganic & medicinal chemistry letters 2009 Dec 16; In press
Brotherton-Pleiss C CE, Dillon M MP, Ford A AP, Gever J JR, Carter D DS, Gleason S SK, Lin C CJ, Moore A AG, Thompson A AW, Villa M, Zhai Y
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.