Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT₁ F receptor agonists: Evolution from bicyclic to monocyclic cores.
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 CO 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.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Deyi
D
Zhang
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: blanco_maria@lilly.com.
Maria-Jesus
MJ
Blanco
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Bai-Ping
BP
Ying
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Daniel
D
Kohlman
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Sidney X
SX
Liang
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Frantz
F
Victor
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Qi
Q
Chen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Joseph
J
Krushinski
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Sandra A
SA
Filla
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Kevin J
KJ
Hudziak
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Brian M
BM
Mathes
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Michael P
MP
Cohen
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
DeAnna
D
Zacherl
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
David L G
DL
Nelson
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
David B
DB
Wainscott
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Suzanne E
SE
Nutter
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Wendy H
WH
Gough
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
John M
JM
Schaus
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
Yao-Chang
YC
Xu
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011789:Quantum Theory; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001549:Benzamides; C000607837:N-(3-(1-methyl-piperidine-4-carbonyl)-phenyl)-benzamide; D010880:Piperidines; D044263:Receptors, Serotonin, 5-HT1; D058825:Serotonin 5-HT1 Receptor Agonists
5-HT(1F); Conformation analysis; Electrostatic and steric interactions; Selectivity; Serotonin