Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists.
A new series of 1,3-dioxane-2-carboxylic acid derivatives was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of 2-methyl-c-5-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid 4b as a potent PPARalpha agonist with high subtype selectivity at human receptor subtypes. This compound exhibited a substantial hypolipidemic effect in type 2 diabetic KK-A(y) mice.
Aoki
Tomiyoshi
T
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-Ku, Kyoto 601-8550, Japan.
Asaki
Tetsuo
T
Hamamoto
Taisuke
T
Sugiyama
Yukiteru
Y
Ohmachi
Shinji
S
Kuwabara
Kenji
K
Murakami
Kohji
K
Todo
Makoto
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D008074:Lipoproteins / Q000097:blood; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D013329:Structure-Activity Relationship; D014280:Triglycerides / Q000097:blood
C529342:2-methyl-c-5-(4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)butyl)-1,3-dioxane-r-2-carboxylic acid; D001786:Blood Glucose; D004146:Dioxanes; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D010080:Oxazoles; D047493:PPAR alpha; D014280:Triglycerides