title: Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives, a novel class of subtype-selective peroxisome proliferator-activated receptor alpha (PPARalpha) agonists.
abstract: A series of 1,3-dioxane carboxylic acid derivatives was synthesized and evaluated for human PPAR transactivation activity. Structure-activity relationships on the phenyloxazole moiety of the lead compound 3 revealed that the introduction of small hydrophobic substituents at the 4-position of the terminal phenyl ring increased the PPARalpha agonist activity, and that the oxazole heterocycle was essential to the maintenance of both potency and PPARalpha subtype-selectivity. This investigation led to the identification of 14d (NS-220) and 14i as highly potent and selective human PPARalpha agonists. In KK-A(y) type 2 diabetic mice, these compounds significantly lowered plasma triglyceride and very-low-density plus low-density lipoprotein cholesterol levels while simultaneously raising HDL cholesterol levels. Our results suggest that highly potent and subtype-selective PPARalpha agonists will be promising drugs for the treatment of metabolic disorders in type 2 diabetes.
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan. t.asaki@po.nippon-shinyaku.co.jp
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Asaki
authors.forename: Tomiyoshi
authors.initials: T
authors.lastname: Aoki
authors.forename: Taisuke
authors.initials: T
authors.lastname: Hamamoto
authors.forename: Yukiteru
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohmachi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwabara
authors.forename: Kohji
authors.initials: K
authors.lastname: Murakami
authors.forename: Makoto
authors.initials: M
authors.lastname: Todo
mesh_terms: D000818:Animals; D020650:Combinatorial Chemistry Techniques; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C487401:2-methyl-c-5-(4-(5-methyl-2-(4-methylphenyl)-4-oxazolyl)butyl)-1,3-dioxane-r-2-carboxylic acid; D004146:Dioxanes; D010080:Oxazoles; D047493:PPAR alpha