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
  • 1. Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: [email protected].
  • 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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