Discovery of highly potent dual EP(2) and EP(3) agonists with subtype selectivity.

Abstract The cyclic carbamate derivatives, 2-{[2-((4 S )-4-{(1E,3 R )-8-fluoro-3-hydroxy-4,4-dimethyl-1-octenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid ( 5 ) and 2-{[2-((4 S )-4-{(1E,3 R )-3-[1-(4-fluorobutyl)cyclobutyl]-3-hydroxy-1-propenyl}-2-oxo-1,3-oxazolidin-3-yl)ethyl]sulfanyl}-1,3-thiazole-4-carboxylic acid ( 7 ) were identified as the first potent dual EP 2 and EP 3 agonists with selectivity against the EP 1 and EP 4 subtypes. Compounds 5 and 7 demonstrated highly potent dual EP 2 and EP 3 agonist activity with EC 50 values of 10 nM or less. In addition, these compounds possess structural features distinct from natural prostaglandins, such as a cyclic carbamate moiety, a dimethyl or cyclobutyl group and a terminal fluorine atom.