Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X(3)/P2X(2/3) antagonist for the treatment of pain.
P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X(3) and P2X(2/3) receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X(3)/P2X(2/3) antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X(3)/P2X(2/3) antagonist.
Carter
David S
DS
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Alam
Muzaffar
M
Cai
Haiying
H
Dillon
Michael P
MP
Ford
Anthony P D W
AP
Gever
Joel R
JR
Jahangir
Alam
A
Lin
Clara
C
Moore
Amy G
AG
Wagner
Paul J
PJ
Zhai
Yansheng
Y
D000255:Adenosine Triphosphate / Q000737:chemistry; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D007477:Ions; D008024:Ligands; 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
D000700:Analgesics; D007477:Ions; D008024:Ligands; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines; C542959:RO-4 compound; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate