[[omega-(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 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.
SmithKline Beecham Pharmaceuticals, Epsom, Surrey, United Kingdom.
B C
BC
Cantello
M A
MA
Cawthorne
G P
GP
Cottam
P T
PT
Duff
D
D
Haigh
R M
RM
Hindley
C A
CA
Lister
S A
SA
Smith
P L
PL
Thurlby
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000032:analysis; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
D006454:Hemoglobins; D007004:Hypoglycemic Agents; D013844:Thiazoles