Yorihisa Hoshino

Synthesis and structure-activity relationships of pyrazolo[1,5-a]pyridine derivatives: potent and orally active antagonists of corticotropin-releasing factor 1 receptor.

Design, synthesis, and structure-activity relationships of a series of 3-dialkylamino-7-phenyl pyrazolo[1,5-a]pyridines (I) as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor are described. The most prominent compound to emerge from this work, 46 (E2508), exhibits potent in vitro activity, excellent drug-like properties, and robust oral efficacy in animal models of stress-related disorders. It has advanced into clinical trials.

Synthesis of (S)-N-(endo-8-methyl-8-azabicyclo[3.2.1]oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyloxy) [carbonyl-14C]benzamide monohydrochloride (14C-E3620)

(S)-N-(endo-8-Methyl-8-azabicyclo[3.2.1]oct-3α-yl)-4-amino-5-chloro-2-(1-methyl-2-butynyloxy)[carbonyl-14C]benzamide monohydrochloride (14C-E3620, 1 1), which was required for a study of the pharmacokinetic profile of E3620, is not only a potent antagonist of 5-HT3 receptors but also a potent agonist of 5-HT4 receptors. It was synthesized using (S)-5-chloro-4-(2,5-dimethylpyrrol-1-yl)-2-(1-methyl-2-butynyloxy)[carboxy-14C]benzoic acid (8) as the labelled starting material.