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

Journal of Medicinal Chemistry, ISSN: 0022-2623, Vol: 51, Issue: 23, Page: 7370-7379
2008
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Article Description

To identify new CRF receptor antagonists, an attempt to modify the bis-hetherocycle moiety present in the top region of the dihydropirrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic hetherocycles 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. © 2008 American Chemical Society.

Bibliographic Details

Di Fabio, Romano; St-Denis, Yves; Sabbatini, Fabio M; Andreotti, Daniele; Arban, Roberto; Bernasconi, Giovanni; Braggio, Simone; Blaney, Frank E; Capelli, Anna M; Castiglioni, Emiliano; Di Modugno, Enza; Donati, Daniele; Fazzolari, Elettra; Ratti, Emiliangelo; Feriani, Aldo; Contini, Stefania; Gentile, Gabriella; Ghirlanda, Damiano; Provera, Stefano; Marchioro, Carla; Roberts, Karen L; Mingardi, Anna; Mattioli, Mario; Nalin, Arnaldo; Pavone, Francesca; Spada, Simone; Trist, David G; Worby, Angela

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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