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

著者: Christa C Chrovian, Akinola Soyode-Johnson, Alexander A Peterson, Christine F. Gelin, Xiaohu Deng, Curt A. Dvorak, Nicholas I. Carruthers, Brian Lord, Ian Fraser, Leah Aluisio, Kevin J Coe, Brian Scott, Tatiana Koudriakova, Freddy Schoetens, Kia Sepassi, David J. Gallacher, Anindya Bhattacharya, and Michael A Letavic

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 14) 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 20), 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 20 had notable solubility compared to 14 and showed good tolerability in preclinical species. Compound 20 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.