Dihydropyridopyrazinones and Dihydropteridinones as Corticotropin-Releasing Factor-1 Receptor Antagonists: Structure-Activity Relationships and Computational Modeling
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- 作者：Carolyn D. Dzierba ; Andrew J. Tebben ; Richard G. Wilde ; Amy G. Takvorian ; Maria Rafalski ; Padmaja Kasireddy-Polam ; John D. Klaczkiewicz ; Anthony D. Pechulis ; Amy L. Davis ; Mark P. Sweet ; Alex M. Woo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：May 3, 2007
- 年：2007
- 卷：50
- 期：9
- 页码：2269 - 2272
- 全文大小：78K
- 年卷期：v.50,no.9(May 3, 2007)
- ISSN：1520-4804
文摘
The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogenand an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potencyagainst the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues.We have derived a two component computational model that correlates CRFR1 binding affinity within thereported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.