Design, synthesis and evaluation of bicyclic benzamides as novel 5-HT1F receptor agonists.
Several fused bicyclic systems have been investigated to serve as the core structure of potent and selective 5-HT1F receptor agonists. Replacement of the indole nucleus in 2 with indazole and 'inverted' indazole provided more potent and selective 5-HT1F receptor ligands. Indoline and 1,2-benzisoxazole systems also provided potent 5-HT1F receptor agonists, and the 5-HT1A receptor selectivity of the indoline- and 1,2-benzisoxazole-based 5-HT1F receptor agonists could be improved with modification of the benzoyl moiety of the benzamides. Through these studies, we found that the inherent geometries of the templates, not the nature of hybridization of the linking atom, were important for the 5-HT1F receptor recognition.
Zhang
Deyi
D
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. zhang_deyi@lilly.com
Kohlman
Dan
D
Krushinski
Joseph
J
Liang
Sidney
S
Ying
Bai-Ping
BP
Reilly
John E
JE
Dinn
Sean R
SR
Wainscott
David B
DB
Nutter
Suzanne
S
Gough
Wendy
W
Nelson
David L G
DL
Schaus
John M
JM
Xu
Yao-Chang
YC
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D015394:Molecular Structure; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000096642:Receptor, Serotonin, 5-HT1F
D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F