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.
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.
Jahangir
Alam
A
Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Alam
Muzaffar
M
Carter
David S
DS
Dillon
Michael P
MP
Bois
Daisy Joe Du
DJ
Ford
Anthony P D W
AP
Gever
Joel R
JR
Lin
Clara
C
Wagner
Paul J
PJ
Zhai
Yansheng
Y
Zira
Jeff
J
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
D000700:Analgesics; D058919:Purinergic P2 Receptor Antagonists; D011743:Pyrimidines; C542960:RO-51 compound; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate