Design and synthesis of a selective EP4-receptor agonist. Part 2: 3,7-dithiaPGE1 derivatives with high selectivity.
To identify new highly selective EP4-agonists, further modification of the 16-phenyl moiety of 1 was continued. 16-(3-methoxymethyl)phenyl derivatives 13-(6q) and 16-(3-ethoxymethyl)phenyl derivatives 13-(7e) showed more selectivity and potent agonist activity than 1. 16-(3-methyl-4-hydroxy)phenyl derivative 18-(14e) demonstrated excellent subtype selectivity, while both its receptor affinity and agonist activity were less potent than those of 13-(6q). Structure-activity relationships (SARs) are also discussed.
Maruyama
Toru
T
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, 618-8585, Osaka, Japan. to.maruyama@ono.co.jp
Asada
Masaki
M
Shiraishi
Tai
T
Ishida
Akiharu
A
Yoshida
Hideyuki
H
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Nakai
Hisao
H
Kondo
Kigen
K
Toda
Masaaki
M
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D011485:Protein Binding; D011869:Radioligand Assay; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013440:Sulfides
C464981:3,7-dithia(11 alpha,13E,15S)-11,15-Dihydroxy-9-oxoprost-13-en-1-oic acid; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013440:Sulfides; D000242:Cyclic AMP; D000527:Alprostadil