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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 6; p. 1632
• Main Authors: Jahangir, Alam, Alam, Muzaffar, Carter, David S, Dillon, Michael P, Bois, Daisy Joe Du, Ford, Anthony P D W, Gever, Joel R, Lin, Clara, Wagner, Paul J, Zhai, Yansheng, Zira, Jeff
• Format: Journal Article
• Language: English
• Published: England 15.03.2009
• Subjects: Adenosine Triphosphate - chemistry; Analgesics - chemical synthesis; Analgesics - pharmacology; Animals; Chemistry, Pharmaceutical - methods; CHO Cells; Cricetinae; Cricetulus; Drug Design; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Models, Chemical; Pain - drug therapy; Purinergic P2 Receptor Antagonists; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Receptors, Purinergic P2 - chemistry; Structure-Activity Relationship
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.097

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.