Identification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective,dual P2X3/P2X2/3 antagonist for the treatment of pain |
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| Authors: | Alam Jahangir Muzaffar Alam David S Carter Michael P Dillon Daisy Joe Du Bois Anthony PDW Ford Joel R Gever Clara Lin Paul J Wagner Yansheng Zhai Jeff Zira |
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| Institution: | 1. Department of Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA;2. Department of Biochemical Pharmacology, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA |
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| Abstract: | The purinoceptor subtypes P2X3 and P2X2/3 have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X3/P2X2/3 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 P2X3/P2X2/3 antagonist RO-51 is presented. |
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