Discovery of a novel EP2/EP4 dual agonist with high subtype-selectivity

A series of γ-lactam prostaglandin E1 analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (Ki values: mEP2 = 9.3 nM, mEP4 = 0.41 nM). A structure–activity relationship study is presented.