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Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists

2008; American Chemical Society; Volume: 51; Issue: 23 Linguagem: Inglês

10.1021/jm800744m

1520-4804

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

Hormonal Regulation and Hypertension

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.