Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1F receptor agonists: Evolution from bicyclic to monocyclic cores
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- 作者：Deyi Zhang ; Maria-Jesus Blanco ; blanco_maria@lilly.com" class="auth_mail" title="E-mail the corresponding author ; Bai-Ping Ying ; Daniel Kohlman ; Sidney X. Liang ; Frantz Victor ; Qi Chen ; Joseph Krushinski ; Sandra A. Filla ; Kevin J. Hudziak ; Brian M. Mathes ; Michael P. Cohen ; DeAnna Zacherl ; David L.G. Nelson ; David B. Wainscott ; Suzanne E. Nutter ; Wendy H. Gough ; John M. Schaus ; Yao-Chang Xu
- 关键词：Serotonin ; Selectivity ; 5-HT1F ; Conformation analysis ; Electrostatic and steric interactions
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：1 October 2015
- 年：2015
- 卷：25
- 期：19
- 页码：4337-4341
- 全文大小：915 K
文摘
Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone C
O group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.
O group play pivotal roles in affecting the adopted conformation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT1F receptor agonists.