Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist.
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.
Brotherton-Pleiss
Christine E
CE
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. brotherton.pleiss@gmail.com
Dillon
Michael P
MP
Ford
Anthony P D W
AP
Gever
Joel R
JR
Carter
David S
DS
Gleason
Shelley K
SK
Lin
Clara J
CJ
Moore
Amy G
AG
Thompson
Anthony W
AW
Villa
Marzia
M
Zhai
Yansheng
Y
D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058477:Receptors, Purinergic P2X3; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology*
C546407:P2RX3 protein, human; D058919:Purinergic P2 Receptor Antagonists; D011720:Pyrazoles; C552197:RO 85 compound; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D013876:Thiophenes