Novel 5-substituted-1H-tetrazole derivatives as potent glucose and lipid lowering agents.
A series of 5-(4-alkoxyphenylalkyl)-1H-tetrazole derivatives, containing an oxazole-based group at the alkoxy moiety, was prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKAy mice and Wistar fatty rats. Syntheses were performed by cyclization of the corresponding nitrites reacting with azide compounds. A large number of the 5-(4-alkoxyphenylalkyl)-1H-tetrazoles showed potent glucose and lipid lowering activities in KKAy mice. In particular, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridyl]propyl]-1H-tetrazole had potent glucose lowering activity (ED25=0.0839 mg x kg(-1) x d(-1)), being 72 times more active than pioglitazone hydrochloride (ED25=6.0 mg x kg(-1) x d(-1)). This compound also showed strong glucose lowering (ED25=0.0873 mg x kg(-1) x d(-1)) and lipid lowering effects (ED25=0.0277 mg x kg(-1) x d(-1)) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (PPARgamma) (EC50 = 6.75 nM).
Momose
Yu
Y
Medicinal Chemistry Research Laboratories II, Product Planning, Strategic Product Planning Department, Takeda Chemical Industries, Ltd., Osaka, Japan. Momose_Yu@takeda.co.jp
Maekawa
Tsuyoshi
T
Odaka
Hiroyuki
H
Ikeda
Hitoshi
H
Sohda
Takashi
T
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood
C460620:5-(3-(6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridyl)propyl)-1H-tetrazole; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013777:Tetrazoles; D014157:Transcription Factors; D014280:Triglycerides; C045574:1H-tetrazole