Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (JNJ 54166060), a Small Molecule Antagonist of the P2X7 receptor

  • J Med Chem. 2016 Sep 22;59(18):8535-48. doi: 10.1021/acs.jmedchem.6b00989.
Devin M Swanson  1 ,  Brad M Savall  1 ,  Kevin J Coe  1 ,  Freddy Schoetens  1 ,  Tatiana Koudriakova  1 ,  Judith Skaptason  1 ,  Jessica Wall  1 ,  Jason Rech  1 ,  Xiahou Deng  1 ,  Meri De Angelis  2 ,  Anita Everson  1 ,  Brian Lord  1 ,  Qi Wang  1 ,  Hong Ao  1 ,  Brian Scott  1 ,  Kia Sepassi  1 ,  Timothy W Lovenberg  1 ,  Nicholas I Carruthers  1 ,  Anindya Bhattacharya  1 ,  Michael A Letavic  1
Affiliations
  • 1. Janssen Pharmaceutical Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121 United States.
  • 2. Janssen Research & Development, Discovery Sciences, A Division of Janssen-Cilag , Jarama 75, 45007 Toledo, Spain.
PMID: 27548392 DOI: 10.1021/acs.jmedchem.6b00989
Abstract

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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