title: Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. brotherton.pleiss@gmail.com
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brotherton-Pleiss
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dillon
authors.forename: Anthony P D W
authors.initials: AP
authors.lastname: Ford
authors.forename: Joel R
authors.initials: JR
authors.lastname: Gever
authors.forename: David S
authors.initials: DS
authors.lastname: Carter
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Gleason
authors.forename: Clara J
authors.initials: CJ
authors.lastname: Lin
authors.forename: Amy G
authors.initials: AG
authors.lastname: Moore
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Thompson
authors.forename: Marzia
authors.initials: M
authors.lastname: Villa
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Zhai
mesh_terms: 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*
chemical_list: 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