title: Synthesis and Structure-Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists.
abstract: We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly 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: Masahiro
authors.initials: M
authors.lastname: Ota
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Setoguchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Kubo
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: Hiroyuki
authors.initials: H
authors.lastname: Usui
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011924:Rats, Zucker; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; C018556:glycine amide; D005998:Glycine