The design and synthesis of a tricyclic single-nitrogen scaffold that serves as a 5-HT2C receptor agonist.
5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.
Huck
Bayard R
BR
Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA. brhuck@hotmail.com
Llamas
Luis
L
Robarge
Michael J
MJ
Dent
Thomas C
TC
Song
Jianping
J
Hodnick
William F
WF
Crumrine
Chris
C
Stricker-Krongrad
Alain
A
Harrington
John
J
Brunden
Kurt R
KR
Bennani
Youssef L
YL
D000818:Animals; D004285:Dogs; D015195:Drug Design; D005247:Feeding Behavior / Q000187:drug effects; D006207:Half-Life; D009584:Nitrogen / Q000737:chemistry*; D051381:Rats; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D009584:Nitrogen