Lead optimization studies of cinnamic amide EP2 antagonists.
Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.
Department of Pharmacology, School of Medicine, Emory University , 1510 Clifton Road, Atlanta, Georgia 30322, United States.
Thota
T
Ganesh
Jianxiong
J
Jiang
Myung-Soon
MS
Yang
Ray
R
Dingledine
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
D000577:Amides; D002934:Cinnamates; D058307:Receptors, Prostaglandin E, EP2 Subtype