1 research outputs found
Identification of (<i>R</i>)‑(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro‑1<i>H</i>‑imidazo[4,5‑<i>c</i>]pyridin-5(4<i>H</i>)‑yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor
The synthesis and
SAR of a series of 4,5,6,7-tetrahydro-imidazoÂ[4,5-<i>c</i>]Âpyridine P2X7 antagonists are described. Addressing P2X7
affinity and liver microsomal stability issues encountered with this
template afforded methyl substituted 4,5,6,7-tetrahydro-imidazoÂ[4,5-<i>c</i>]Âpyridines ultimately leading to the identification of <b>1</b> (JNJ 54166060). <b>1</b> is a potent P2X7 antagonist
with an ED<sub>50</sub> = 2.3 mg/kg in rats, high oral bioavailability
and low-moderate clearance in preclinical species, acceptable safety
margins in rats, and a predicted human dose of 120 mg of QD. Additionally, <b>1</b> possesses a unique CYP profile and was found to be a regioselective
inhibitor of midazolam CYP3A metabolism