[摘要]：To identify new CRF1 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 CRF1 receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compds., was replaced by more hydrophilic non arom. heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate anal. of the substitution of the pendant aryl ring, enabled identification of in vitro potent compds., e.g., I, showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.
