title: Design, synthesis and evaluation of bicyclic benzamides as novel 5-HT1F receptor agonists.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. zhang_deyi@lilly.com
authors.forename: Deyi
authors.initials: D
authors.lastname: Zhang
authors.forename: Dan
authors.initials: D
authors.lastname: Kohlman
authors.forename: Joseph
authors.initials: J
authors.lastname: Krushinski
authors.forename: Sidney
authors.initials: S
authors.lastname: Liang
authors.forename: Bai-Ping
authors.initials: BP
authors.lastname: Ying
authors.forename: John E
authors.initials: JE
authors.lastname: Reilly
authors.forename: Sean R
authors.initials: SR
authors.lastname: Dinn
authors.forename: David B
authors.initials: DB
authors.lastname: Wainscott
authors.forename: Suzanne
authors.initials: S
authors.lastname: Nutter
authors.forename: Wendy
authors.initials: W
authors.lastname: Gough
authors.forename: David L G
authors.initials: DL
authors.lastname: Nelson
authors.forename: John M
authors.initials: JM
authors.lastname: Schaus
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Xu
mesh_terms: 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
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000096642:Receptor, Serotonin, 5-HT1F