Document Report Card

ID: ALA1140209

Journal: J Med Chem

Title: Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.

Authors: Di Fabio R, St-Denis Y, Sabbatini FM, Andreotti D, Arban R, Bernasconi G, Braggio S, Blaney FE, Capelli AM, Castiglioni E, Di Modugno E, Donati D, Fazzolari E, Ratti E, Feriani A, Contini S, Gentile G, Ghirlanda D, Provera S, Marchioro C, Roberts KL, Mingardi A, Mattioli M, Nalin A, Pavone F, Spada S, Trist DG, Worby A.

Abstract: To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.

CiteXplore: 18989952

DOI: 10.1021/jm800744m