| Autor: |
Chrovian CC; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Soyode-Johnson A; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Peterson AA; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Gelin CF; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Deng X; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Dvorak CA; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Carruthers NI; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Lord B; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Fraser I; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Aluisio L; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Coe KJ; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Scott B; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Koudriakova T; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Schoetens F; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Sepassi K; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Gallacher DJ; Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, 2340 Beerse, Belgium., Bhattacharya A; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States., Letavic MA; Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States. |
| Abstrakt: |
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 ED 50 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. |
