The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists

Porter, David W, Bradley, Michelle, Brown, Zarin, Canova, Riccardo, Charlton, Steven, Cox, Brian, Hunt, Peter, Kolarik, David, Lewis, Sarah, O'Connor, Des, Reilly, John, Spanka, Carsten, Tedaldia, Lauren, Watson, Simon J, Wermuth, Roland and Press, Neil J (2014) The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists. Bioorganic & Medicinal Chemistry Letters, 24 (1). pp. 72-76. ISSN 0960-894X

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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 1, 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 14. 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
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry
Depositing User: Tom Gittoes
Date Deposited: 12 Jan 2015 11:45
Last Modified: 12 Jan 2015 11:45
URI: http://sro.sussex.ac.uk/id/eprint/52040
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