Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE1 and 9-β-halo derivatives with improved stability Original Research Article

To identify a new selective EP4-agonist with improved chemical stability, further chemical modification of those reported previously was continued. We focused our attention on chemical modification of the α chain of 3,7-dithiaPGE1 and selected 5-thiaPGE1 as a new chemical lead. Introduction of an optimized ω chain to the 5-thiaPG skeleton afforded m-methoxymethyl derivative , which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9β-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the β-hydroxyketone moiety. Among these series, and 39b showed potent agonist activity and good subtype-selectivity. Structure–activity relationships (SARs) are also discussed.