title: The discovery of potent, orally bioavailable pyrimidine-5-carbonitrile-6-alkyl CXCR2 receptor antagonists.
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.
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom. Electronic address: david.porter@novartis.com.
authors: David W
authors: DW
authors: Porter
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Michelle
authors: M
authors: Bradley
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Zarin
authors: Z
authors: Brown
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Steven J
authors: SJ
authors: Charlton
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Brian
authors: B
authors: Cox
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Peter
authors: P
authors: Hunt
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Diana
authors: D
authors: Janus
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Sarah
authors: S
authors: Lewis
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Paul
authors: P
authors: Oakley
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Des
authors: D
authors: O'Connor
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: John
authors: J
authors: Reilly
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Nichola
authors: N
authors: Smith
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Neil J
authors: NJ
authors: Press
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C000595736:2-((2,3-difluorobenzyl)thio)-6-(2-(hydroxymethyl)cyclopropyl)-5-isocyanopyrimidin-4-ol; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B
keywords: COPD; CXCR2; Chemokines; Neutrophils; Pyrimidine