2. Academic Validation
  3. 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

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

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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