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The Discovery of Potent, Orally Bioavailable Pyrazolo and Triazolopyrimidine CXCR2 Receptor Antagonists.

Porter, David and Bradley, Michelle and Brown, Zarin and Canova, Riccardo and Charlton, Steven and Cox, Brian and Hunt, Peter and Kolarik, David and Lewis, Sarah and O'Connor, Des and Reilly, John and Spanka, Carsten and Tedaldi, Lauren and Watson, Simon and Wermuth, Roland and Press, Neil (2014) The Discovery of Potent, Orally Bioavailable Pyrazolo and Triazolopyrimidine CXCR2 Receptor Antagonists. Biorganic and Medicinal Chemistry Letters, 24 (1). pp. 72-76.

Abstract

A Hit-to-Lead optimisation programme was carried out on the Novartis archive screening hit, pyrazolopyrimidine 2-methyl-5-((phenylthio)methyl)pyrazolo[1,5-a]pyrimidin-7-ol, resulting in the discovery of CXCR2 receptor antagonist 2-benzyl-5-(((2,3-difluorophenyl)thio)methyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol. The SAR was investigated by systematic variation of the pendant thiol, alkyl and pyrimidinol groups. Replacement of the pyrazolopyrimidine core with a triazolo alternative led to a dual series of antagonists with favourable biological and pharmacokinetic properties.

Item Type: Article
Keywords: CXCR2 receptor Antagonists
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10727

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