Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE(1) and 9-beta-halo derivatives with improved stability

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 6; pp. 1743 - 1759
• Main Authors: Maruyama, Toru, Asada, Masaki, Shiraishi, Tai, Yoshida, Hideyuki, Maruyama, Takayuki, Ohuchida, Shuichi, Nakai, Hisao, Kondo, Kigen, Toda, Masaaki
• Format: Journal Article
• Language: English
• Published: England 01.06.2002
• Subjects: Animals; Calcium - metabolism; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Drug Design; Drug Stability; Molecular Structure; Prostaglandins E, Synthetic - chemical synthesis; Prostaglandins E, Synthetic - chemistry; Prostaglandins E, Synthetic - pharmacology; Receptors, Prostaglandin E - agonists; Receptors, Prostaglandin E - metabolism; Receptors, Prostaglandin E, EP4 Subtype; Second Messenger Systems - drug effects; Structure-Activity Relationship; Substrate Specificity
• ISSN: 0968-0896
• DOI: 10.1016/S0968-0896(02)00031-7

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 alpha chain of 3,7-dithiaPGE(1) and selected 5-thiaPGE(1) as a new chemical lead. Introduction of an optimized omega chain to the 5-thiaPG skeleton afforded m-methoxymethyl derivative 33a, which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9beta-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the beta-hydroxyketone moiety. Among these series, and 39b showed potent agonist activity and good subtype-selectivity. Structure-activity relationships (SARs) are also discussed.