Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1).
We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR α/γ dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR α/γ dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR α/γ dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model.
Lead Discovery and Optimization Research Laboratories II, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. shibata.yoshihiro.da@daiichisankyo.co.jp
Yoshihiro
Y
Shibata
Katsuji
K
Kagechika
Mitsuhiro
M
Yamaguchi
Hideo
H
Kubo
Hiroyuki
H
Usui
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015195:Drug Design; D051379:Mice; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D001786:Blood Glucose; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides