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Dihydropyrrole[2,3- d ]pyridine Derivatives as Novel Corticotropin-Releasing Factor-1 Antagonists: Mapping of the Receptor Binding Pocket by in Silico Docking Studies

2008; American Chemical Society; Volume: 51; Issue: 22 Linguagem: Inglês

10.1021/jm800743q

1520-4804

Romano Di Fabio, Roberto Arban, Giovanni Bernasconi, Simone Braggio, Frank E. Blaney, Anna Maria Capelli, Emiliano Castiglioni, Daniele Donati, Elettra Fazzolari, Emiliangelo Ratti, Aldo Feriani, Stefania Contini, Gabriella Gentile, Damiano Ghirlanda, Fabio Maria Sabbatini, Daniele Andreotti, Simone Spada, Carla Marchioro, Angela Worby, Yves St‐Denis,

Hormonal Regulation and Hypertension

In an effort to discover novel CRF-1 receptor antagonists exhibiting improved physicochemical properties, a dihydropirrole[2,3]pyridine scaffold was designed and explored in terms of the SAR of the substitution at the pendent phenyl ring and the nature of the heterocyclic moieties present in the upper region of the molecule. Selective and potent compounds have been discovered endowed with reduced ClogP with respect to compounds known in the literature. Of particular relevance was the finding that the in vitro affinity of the series was maintained by reducing the overall lipophilicity. The results achieved by this exploration enabled the formulation of a novel hypothesis on the nature of the receptor binding pocket of this class of CRF-1 receptor antagonists, making use of in silico docking studies of the putative nonpeptidic antagonist binding site set up in house by homology modeling techniques.