Development of a highly selective EP2-receptor agonist. Part 2: identification of 16-hydroxy-17,17-trimethylene 9beta-chloro PGF derivatives.
Further chemical modification of 1a and 2 was undertaken to identify a more chemically stable selective EP2-receptor agonist for development as a clinical candidate. 9beta-chloro PG analogues 4a-e and 5a, c-e were found to be potent and selective EP2-receptor agonists. Among them, the compound 4aLy, which is a chemically stabilized lysine salt of 4a, exhibited an excellent profile both in biological activities and physicochemical properties. The agonist 4aLy was found to suppress uterine motility in anesthetized pregnant rats, while PGE2 stimulated uterine motility. Structure-activity relationships (SARs) are discussed.
Tani
Kousuke
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, 618-8585, Osaka, Japan. k.tani@ono.co.jp
Naganawa
Atsushi
A
Ishida
Akiharu
A
Egashira
Hiromu
H
Sagawa
Kenji
K
Harada
Hiroyuki
H
Ogawa
Mikio
M
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Nakai
Hisao
H
Kondo
Kigen
K
Toda
Masaaki
M
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D011247:Pregnancy; D011461:Prostaglandins F, Synthetic / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014590:Uterine Contraction / Q000187:drug effects
D011461:Prostaglandins F, Synthetic; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000242:Cyclic AMP