Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X3/P2X2/3 antagonist for the treatment of pain
Graphical abstract
The discovery and structure–activity relationships of a novel series of diaminopyrimidine based dual P2X3/P2X2/3 antagonists is described.
References and notes (19)
- et al.
Pain
(1999) - et al.
Adv. Drug. Del. Rev.
(1997)(b)This series meets all the criteria defined by Lipinski for drug-likeness. As a result RO-4 exhibited good oral... - et al.
Chem. Eur. J.
(1997)et al.Tetrahedron
(1996) - et al.
Pfluegers Archiv.
(2006) Mol. Pharmacol.
(2007)- et al.
Nature
(2000) - et al.
J. Neurosci.
(2002) - et al.
Nucl. Acids Res.
(2004) - et al.
Mol. Pharmacol.
(1998)
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