[[ω-(Heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones as potent antihyperglycemic agents

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]-benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of the type suc...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-11, Vol.37 (23), p.3977-3985
Main Authors: CANTELLO, B. C. C, CAWTHORNE, M. A, COTTAM, G. P, DUFF, P. T, HAIGH, D, HINDLEY, R. M, LISTER, C. A, SMITH, S. A, THURLBY, P. L
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chemistry
Diabetes Mellitus, Type 2 - drug therapy
Disease Models, Animal
Exact sciences and technology
General and cellular metabolism. Vitamins
Hemoglobins - analysis
Heterocyclic compounds
Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
Medical sciences
Mice
Mice, Inbred C57BL
Organic chemistry
Pharmacology. Drug treatments
Preparations and properties
Structure-Activity Relationship
Thiazoles - pharmacology
Thiazoles - therapeutic use
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Summary:A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]-benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045). The benzoxazole 49, a cyclic analogue of 16, was a very potent enhancer of insulin sensitivity, and by modification of the aromatic heterocycle, an aminopyridine, 37, was identified as a lead compound from SAR studies. Evaluation of antihyperglycemic activity together with effects on blood hemoglobin content, to determine the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 Bl/6 ob/ob mice. From these studies, BRL 49653 (37) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against reductions in blood hemoglobin content, for further evaluation.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00049a017