Antihyperglycemic activity of new 1,2,4-oxadiazolidine-3,5-diones.
A series of 1,2,4-oxadiazolidine-3,5-diones was synthesized and evaluated as oral antihyperglycemic agents in the obese insulin resistant db/db and ob/ob mouse - the two models for Type 2 diabetes mellitus. The majority of the prepared methoxy- and ethoxy-linked oxazole 1,2,4-oxadiazolidine-3,5-diones normalized plasma glucose levels at the 100 mg kg(-1) oral dose in the db/db diabetic mouse model, and several amongst them reduced the glucose levels at the 20 mg kg(-1) oral dose. The most potent compounds in the db/db mouse model were also active in the ob/ob mouse model normalizing the plasma glucose levels at the 20 mg kg(-1) oral dose. The trifluoromethoxy analog 32 was the most active compound of the series, reducing significantly the plasma glucose levels at the 5 mg kg(-1) oral dose. Oxadiazole-tailed 1,2,4-oxadiazolidine-3,5-diones were also active in both the db/db and ob/ob diabetic mouse models normalizing plasma glucose levels at the 100 mg kg(-1) oral dose.
Wyeth-Ayerst Research Inc., CN 8000, Princeton, NJ 08543-8000, USA. malamam@war.wyeth.com
M S
MS
Malamas
J
J
Sredy
M
M
McCaleb
I
I
Gunawan
B
B
Mihan
D
D
Sullivan
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010069:Oxadiazoles; D013844:Thiazoles; D045162:Thiazolidinediones; C039671:ciglitazone