2. Academic Validation
  3. Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists

Discovery of Novel 1-Cyclopentenyl-3-phenylureas as Selective, Brain Penetrant, and Orally Bioavailable CXCR2 Antagonists

  • J Med Chem. 2018 Mar 22;61(6):2518-2532. doi: 10.1021/acs.jmedchem.7b01854.
Hongfu Lu 1,  Ting Yang 1,  Zhongmiao Xu 1,  Xichen Lin 1,  Qian Ding 1,  Yueting Zhang 2,  Xin Cai 3,  Kelly Dong 3,  Sophie Gong 3,  Wei Zhang 3,  Metul Patel 4,  Royston C B Copley 5,  Jianing Xiang 1,  Xiaoming Guan 1,  Paul Wren 6,  Feng Ren 1
Affiliations

Affiliations

  • 1 Neurosciences Therapeutic Area Unit , GSK Pharmaceuticals R&D , 898 Halei Road, Zhangjiang Hi-Tech Park , Pudong , Shanghai 201203 , P. R. China.
  • 2 R&D Projects Clinical Platforms and Sciences , GSK Pharmaceuticals R&D , 898 Halei Road, Zhangjiang Hi-Tech Park , Pudong , Shanghai 201203 , P. R. China.
  • 3 Platform Technology Sciences , GSK Pharmaceuticals R&D , 898 Halei Road, Zhangjiang Hi-Tech Park , Pudong , Shanghai 201203 , P. R. China.
  • 4 Platform Technology Sciences , GSK Pharmaceuticals R&D , Stevenage , Hertfordshire SG1 2NY , U.K.
  • 5 Platform Technology & Science , GSK Medicines Research Centre , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.
  • 6 Neurosciences Therapeutic Area Unit , GSK Pharmaceuticals R&D , 1250 South Collegeville Road , Collegeville , Pennsylvania 19426 , United States.
PMID: 29406702 DOI: 10.1021/acs.jmedchem.7b01854
Abstract

CXCR2 has emerged as a therapeutic target for not only peripheral inflammatory diseases but also neurological abnormalities in the central nervous system (CNS). Herein, we describe the discovery of a novel 1-cyclopentenyl-3-phenylurea series as potent and CNS penetrant CXCR2 antagonists. Extensive SAR studies, wherein molecules' property forecast index (PFI) was carefully optimized for overall balanced developability profiles, led to the discovery of the advanced lead compound 68 with a desirable PFI. Compound 68 demonstrated good in vitro pharmacology with excellent selectivity over CXCR1 and Other chemokine receptors. Rat and dog pharmacokinetics (PK) revealed good oral bioavailability, high oral exposure, and desirable elimination half-life of the compound in both species. In addition, the compound demonstrated dose-dependent efficacy in the in vivo pharmacology neutrophil infiltration "air pouch" model in rodents after oral administration. Further, compound 68 is a CNS penetrant molecule with high unbound fraction in brain tissue.

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