title: The discovery of potent, orally bioavailable pyrazolo and triazolopyrimidine CXCR2 receptor antagonists.
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.
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, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland.
authors: Riccardo
authors: R
authors: Canova
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Steven
authors: S
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, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland.
authors: David
authors: D
authors: Kolarik
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: 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, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland.
authors: Carsten
authors: C
authors: Spanka
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Lauren
authors: L
authors: Tedaldi
authors: Novartis Institutes for BioMedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom.
authors: Simon J
authors: SJ
authors: Watson
authors: Novartis Institutes for BioMedical Research, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland.
authors: Roland
authors: R
authors: Wermuth
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; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D054390:Receptors, CCR2
keywords: COPD; CXCR2; Chemokines; Neutrophils; Pyrazolopyrimidine; Triazolopyrimidine