Journal of Medicinal Chemistry p. 8535 - 8548 (2016)
Update date:2022-08-15
Topics:
Swanson, Devin M.
Savall, Brad M.
Coe, Kevin J.
Schoetens, Freddy
Koudriakova, Tatiana
Skaptason, Judith
Wall, Jessica
Rech, Jason
Deng, Xiahou
De Angelis, Meri
Everson, Anita
Lord, Brian
Wang, Qi
Ao, Hong
Scott, Brian
Sepassi, Kia
Lovenberg, Timothy W.
Carruthers, Nicholas I.
Bhattacharya, Anindya
Letavic, Michael A.
The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 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, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.
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