ABSTRACT
A series of novel benzamide derivatives, altering the 4-fluorophenylalkyl moiety in cisapride, were synthesized as 5-HT4 receptor agonists, and SAR of these analogs was examined on in vitro and in vivo prokinetic activities. These compounds were synthesized for high 5-HT4 receptor binding affinities and low hERG affinities. Several types of analogs were obtained and screened for 5-HT4 binding, hERG blocking, agonism, and gastric emptying assessment. Among the analogues, compound 23g showed promising results compared with the other analogs with respect to gastric emptying rates in rats. Therefore, we suggest that it may be a clinical candidate for the development of a potent prokinetic agent to treat GI disorders.
Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Gastric Emptying/drug effects , Piperidines/chemistry , Piperidines/pharmacology , Serotonin 5-HT4 Receptor Agonists/chemistry , Serotonin 5-HT4 Receptor Agonists/pharmacology , Animals , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Male , Rats, Sprague-Dawley , Receptors, Serotonin, 5-HT4/metabolism , Structure-Activity RelationshipABSTRACT
[reaction: see text] 3,5-Dibromo-2-pyrone underwent facile Pd(0)-catalyzed coupling reactions with various alkynes to give rise to the corresponding 3-alkynyl-5-bromo-2-pyrones with good to excellent chemical yields and regioselectivity.
ABSTRACT
D-A cycloadditions of 3,5-dibromo-2-pyrone were investigated with a series of electronically and sterically distinct dienophiles. Our results showed that it is a highly potent ambident diene, being more reactive and stereoselective than monobromo-2-pyrones, and thus capable of generating a variety of bicycloadducts in much higher chemical yields and endo/exo ratios than monobromo-2-pyrones. Another interesting feature of this study is that the two bromine groups on the cycloadducts could be independently manipulated to produce other synthetically useful bicyclolactones.
