Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE(1) and 9-beta-halo derivatives with improved stability.
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.
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
Yoshida
Hideyuki
H
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Nakai
Hisao
H
Kondo
Kigen
K
Toda
Masaaki
M
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D015394:Molecular Structure; D011459:Prostaglandins E, Synthetic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018078:Receptors, Prostaglandin E / Q000819:agonists* / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015290:Second Messenger Systems / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D011459:Prostaglandins E, Synthetic; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; D002118:Calcium