title: Identification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective, dual P2X(3)/P2X(2/3) antagonist for the treatment of pain.
abstract: The purinoceptor subtypes P2X(3) and P2X(2/3) have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X(3)/P2X(2/3) diaminopyrimidine antagonist RO-4 prompted subsequent optimization of the template. This paper describes the SAR and optimization of the diaminopyrimidine ring and particularly the substitution of the 2-amino group. The discovery of the highly potent and drug-like dual P2X(3)/P2X(2/3) antagonist RO-51 is presented.
authors.affiliation: Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
authors.forename: Alam
authors.initials: A
authors.lastname: Jahangir
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Alam
authors.forename: David S
authors.initials: DS
authors.lastname: Carter
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dillon
authors.forename: Daisy Joe Du
authors.initials: DJ
authors.lastname: Bois
authors.forename: Anthony P D W
authors.initials: AP
authors.lastname: Ford
authors.forename: Joel R
authors.initials: JR
authors.lastname: Gever
authors.forename: Clara
authors.initials: C
authors.lastname: Lin
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wagner
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Zhai
authors.forename: Jeff
authors.initials: J
authors.lastname: Zira
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010146:Pain / Q000188:drug therapy*; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines; C542960:RO-51 compound; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate