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 <b>68</b> with a desirable PFI. Compound <b>68</b> 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 <b>68</b> is a CNS penetrant
molecule with high unbound fraction in brain tissue
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