2. Academic Validation
  3. The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists

The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists

  • Bioorg Med Chem Lett. 2014 Aug 1;24(15):3285-90. doi: 10.1016/j.bmcl.2014.06.011.
David W Porter 1,  Michelle Bradley 2,  Zarin Brown 2,  Steven J Charlton 2,  Brian Cox 2,  Peter Hunt 2,  Diana Janus 2,  Sarah Lewis 2,  Paul Oakley 2,  Des O'Connor 2,  John Reilly 2,  Nichola Smith 2,  Neil J Press 2
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: david.porter@novartis.com.
  • 2 Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
PMID: 24974342 DOI: 10.1016/j.bmcl.2014.06.011
Abstract

A hit-to-lead optimisation programme was carried out on the Novartis archive screening hit, pyrimidine 2-((2,6-dichlorobenzyl)thio)-5-isocyano-6-phenylpyrimidin-4-ol 4, resulting in the discovery of CXCR2 receptor antagonist 2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol 24. The SAR was investigated by systematic variation of the aromatic group at c-6, the linker between c-2 and the halogenated ring, and the c-5 nitrile moiety.

Keywords

COPD; CXCR2; Chemokines; Neutrophils; Pyrimidine.

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