Synthesis and Pharmacological Characterization of Novel Druglike Corticotropin-Releasing Factor 1 Antagonists
| Autor: | Stefania Contini, Emiliangelo Ratti, Aldo Feriani, Frank E. Blaney, David G. Trist, Karen L Roberts, Fabio Maria Sabbatini, Romano Di Fabio, Damiano Ghirlanda, Daniele Donati, Angela Worby, Stefano Provera, Mario Mattioli, Yves St-Denis, Roberto Arban, Elettra Fazzolari, Emiliano Castiglioni, Francesca Pavone, Simone Spada, Enza Di Modugno, Carla Marchioro, Giovanni Bernasconi, Arnaldo Nalin, Anna Mingardi, Anna Maria Capelli, Daniele Andreotti, Simone Braggio, Gabriella Gentile |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Molecular model Pyridines Stereochemistry Stereoisomerism Motor Activity Receptors Corticotropin-Releasing Hormone Chemical synthesis Rats Sprague-Dawley chemistry.chemical_compound In vivo Forelimb Drug Discovery Animals Humans Moiety Pyrroles Ultrasonics Receptor Psychological Tests Dose-Response Relationship Drug Molecular Structure Chemistry Aryl In vitro Rats Models Chemical Exploratory Behavior Molecular Medicine Female Vocalization Animal Gerbillinae |
| Zdroj: | Journal of Medicinal Chemistry. 51:7370-7379 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800744m |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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