Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of N(3)-Phenylpyrazinones as Novel Corticotropin-Releasing Factor-1 (CRF(1)) Receptor Antagonists. Journal of medicinal chemistry [J Med Chem] Journal article | | Title | Synthesis, Structure-Activity Relationships, and In Vivo Evaluation of N(3)-Phenylpyrazinones as Novel Corticotropin-Releasing Factor-1 (CRF(1)) Receptor Antagonists. | | Author(s) | Hartz RA, Ahuja VT, Arvanitis AG, Rafalski M, Yue EW, Denhart DJ, Schmitz WD, Ditta JL, Deskus JA, Brenner AB, Hobbs FW, Payne J, Lelas S, Li YW, Molski TF, Mattson GK, Peng Y, Wong H, Grace JE, Lentz KA, Qian-Cutrone J, Zhuo X, Shu YZ, Lodge NJ, Zaczek R, Combs AP, Olson RE, Bronson JJ, Mattson RJ, Macor JE | | Institution | Neuroscience Discovery Chemistry. | | Source | J Med Chem 2009 Jun 24. | | Abstract | Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19552437 |
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