Synthesis and evaluation of novel modified γ-lactam prostanoids as EP4 subtype-selective agonists.
To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified γ-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the γ-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. kanbe@ono.co.jp
Tohru
T
Kambe
Toru
T
Maruyama
Toshihiko
T
Nagase
Seiji
S
Ogawa
Chiaki
C
Minamoto
Kiyoto
K
Sakata
Takayuki
T
Maruyama
Hisao
H
Nakai
Masaaki
M
Toda
D000284:Administration, Oral; D000818:Animals; D007769:Lactams / Q000737:chemistry*; D011453:Prostaglandins / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D007769:Lactams; D011453:Prostaglandins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha