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J Med Chem. 2008 Dec 11;51(23):7370-9. doi: 10.1021/jm800744m.

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

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Neurosciences Centre of Excellence for Drug Discovery and Molecular Discovery Research, GlaxoSmithKline Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy.


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.

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