title: Synthesis and structure-activity relationships of novel zwitterionic compounds as peroxisome proliferator activated receptor α/γ dual agonists with improved physicochemical properties.
abstract: We describe herein 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. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Katsuji
authors.initials: K
authors.lastname: Kagechika
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Chiba
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Takano
authors.forename: Chiyuki
authors.initials: C
authors.lastname: Akiyama
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Mina
authors.initials: M
authors.lastname: Nishi
authors.forename: Hideo
authors.initials: H
authors.lastname: Kubo
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Usui
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; D047493:PPAR alpha; D047495:PPAR gamma; C583463:1,3,4-oxadiazole