Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives.
A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKA(y) mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-gamma. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p<0.01) and plasma triglycelide levels (43%, p<0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.
Imoto
Hiroshi
H
Takeda Chemical Industries, Ltd., Pharmaceutical Research Division, Osaka, Japan. Imoto_Hiroshi@takeda.co.jp
Imamiya
Eikoh
E
Momose
Yu
Y
Sugiyama
Yasuo
Y
Kimura
Hiroyuki
H
Sohda
Takashi
T
D019342:Acetic Acid / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D007098:Imino Acids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008820:Mice, Obese; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D007098:Imino Acids; D013844:Thiazoles; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D019342:Acetic Acid