Design and synthesis of a selective EP4-Receptor agonist. Part 1: discovery of 3,7-DithiaPGE1 derivatives and identification of Their ω chains

• Published in: Bioorganic & medicinal chemistry 2002-04, Vol.10 (4), p.975-988
• Main Authors: Maruyama, Toru, Asada, Masaki, Shiraishi, Tai, Egashira, Hiromu, Yoshida, Hideyuki, Maruyama, Takayuki, Ohuchida, Shuichi, Nakai, Hisao, Kondo, Kigen, Toda, Masaaki
• Format: Article
• Language: English
• Subjects: Alprostadil - analogs & derivatives; Alprostadil - chemistry; Alprostadil - pharmacology; Animals; Biological and medical sciences; Calcium - analysis; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Drug Design; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protein Binding; Receptors, Prostaglandin E - agonists; Receptors, Prostaglandin E - metabolism; Receptors, Prostaglandin E, EP4 Subtype; Structure-Activity Relationship; Sulfides
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(01)00351-0

Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the α chain of PGE1 was investigated. Among the compounds tested, 3,7-dithiaPGE14a exhibited good EP4-receptor selectivity and agonist activity. Further modification of the ω chain of 3,7-dithiaPGE1 was performed to improve EP4-receptor selectivity and agonist activity. Of the compounds produced, 16-phenyl-ω-tetranor-3,7-dithiaPGE14p possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety. 3,7-DithiaPGE1 analogues 4a and 4p were discovered as a new chemical lead for development of selective EP4-receptor agonists.