2. Academic Validation
  3. A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

  • J Med Chem. 2018 Jan 11;61(1):207-223. doi: 10.1021/acs.jmedchem.7b01279.
Christa C Chrovian 1,  Akinola Soyode-Johnson 1,  Alexander A Peterson 1,  Christine F Gelin 1,  Xiaohu Deng 1,  Curt A Dvorak 1,  Nicholas I Carruthers 1,  Brian Lord 1,  Ian Fraser 1,  Leah Aluisio 1,  Kevin J Coe 1,  Brian Scott 1,  Tatiana Koudriakova 1,  Freddy Schoetens 1,  Kia Sepassi 1,  David J Gallacher 2,  Anindya Bhattacharya 1,  Michael A Letavic 1
Affiliations

Affiliations

  • 1 Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.
  • 2 Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium.
PMID: 29211470 DOI: 10.1021/acs.jmedchem.7b01279
Abstract

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 Receptor occupancy at low doses in rat with ED50 values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.

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