4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate

  • J Med Chem. 2017 Jun 8;60(11):4559-4572. doi: 10.1021/acs.jmedchem.7b00408.
Michael A Letavic  1 ,  Brad M Savall  1 ,  Brett D Allison  1 ,  Leah Aluisio  1 ,  Jose Ignacio Andres  2 ,  Meri De Angelis  2 ,  Hong Ao  1 ,  Derek A Beauchamp  3 ,  Pascal Bonaventure  1 ,  Stewart Bryant  3 ,  Nicholas I Carruthers  1 ,  Marc Ceusters  4 ,  Kevin J Coe  1 ,  Curt A Dvorak  1 ,  Ian C Fraser  1 ,  Christine F Gelin  1 ,  Tatiana Koudriakova  1 ,  Jimmy Liang  1 ,  Brian Lord  1 ,  Timothy W Lovenberg  1 ,  Monicah A Otieno  3 ,  Freddy Schoetens  1 ,  Devin M Swanson  1 ,  Qi Wang  1 ,  Alan D Wickenden  1 ,  Anindya Bhattacharya  1
Affiliations
  • 1. Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
  • 2. Janssen Research & Development, a Division of Janssen-Cilag , Jarama 75, 45007 Toledo, Spain.
  • 3. Janssen Research & Development, LLC , 1400 McKean Road, Spring House, Pennsylvania 19477, United States.
  • 4. Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
PMID: 28493698 DOI: 10.1021/acs.jmedchem.7b00408
Abstract

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several Other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.

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