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

• Published in: Journal of medicinal chemistry Vol. 61; no. 1; pp. 207 - 223
• Main Authors: Chrovian, Christa C, Soyode-Johnson, Akinola, Peterson, Alexander A, Gelin, Christine F, Deng, Xiaohu, Dvorak, Curt A, Carruthers, Nicholas I, Lord, Brian, Fraser, Ian, Aluisio, Leah, Coe, Kevin J, Scott, Brian, Koudriakova, Tatiana, Schoetens, Freddy, Sepassi, Kia, Gallacher, David J, Bhattacharya, Anindya, Letavic, Michael A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.01.2018; Amer Chemical Soc
• Subjects: Animals; Chemistry, Medicinal; Cycloaddition Reaction; Dogs; Drug Design; Humans; Life Sciences & Biomedicine; Male; Mice; Models, Molecular; Molecular Conformation; Pharmacology & Pharmacy; Purinergic P2X Receptor Antagonists - chemical synthesis; Purinergic P2X Receptor Antagonists - chemistry; Purinergic P2X Receptor Antagonists - pharmacokinetics; Purinergic P2X Receptor Antagonists - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Receptors, Purinergic P2X7 - metabolism; Science & Technology; Stereoisomerism; Tissue Distribution; RHEUMATOID-ARTHRITIS; EFFICACY; SAFETY; PHARMACOLOGICAL CHARACTERIZATION; CLICK CHEMISTRY; DISEASE; RECEPTOR; IDENTIFICATION; AZIDE

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...