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

Devin M Swanson; Brad M Savall; Kevin J Coe; Freddy Schoetens; Tatiana Koudriakova; Judith Skaptason; Jessica Wall; Jason Rech; Xiahou Deng; Meri De Angelis; Anita Everson; Brian Lord; Qi Wang; Hong Ao; Brian Scott; Kia Sepassi; Timothy W Lovenberg; Nicholas I Carruthers; Anindya Bhattacharya; Michael A Letavic

doi:10.1021/acs.jmedchem.6b00989

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. Epub 2016 Sep 8.

Authors

Devin M Swanson¹, Brad M Savall¹, Kevin J Coe¹, Freddy Schoetens¹, Tatiana Koudriakova¹, Judith Skaptason¹, Jessica Wall¹, Jason Rech¹, Xiahou Deng¹, Meri De Angelis², Anita Everson¹, Brian Lord¹, Qi Wang¹, Hong Ao¹, Brian Scott¹, Kia Sepassi¹, Timothy W Lovenberg¹, Nicholas I Carruthers¹, Anindya Bhattacharya¹, Michael A Letavic¹

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.

MeSH terms

Administration, Oral
Animals
Dogs
Halogenation
Haplorhini
Humans
Imidazoles / administration & dosage
Imidazoles / chemistry
Imidazoles / pharmacokinetics
Imidazoles / pharmacology
Mice
Models, Molecular
Purinergic P2X Receptor Antagonists / administration & dosage
Purinergic P2X Receptor Antagonists / chemistry*
Purinergic P2X Receptor Antagonists / pharmacokinetics
Purinergic P2X Receptor Antagonists / pharmacology*
Pyridines / administration & dosage
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Rats
Receptors, Purinergic P2X7 / metabolism*

Substances

Imidazoles
Purinergic P2X Receptor Antagonists
Pyridines
Receptors, Purinergic P2X7