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

B.C.C. Cantello, M.A. Cawthorne, G.P. Cottam, P.T. Duff, David Haigh, R.M. Hindley, C.A. Lister, S.A. Smith, P.L. Thurlby

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278 Citations (Scopus)

Abstract

A series of [(ureidoethoxy)benzyl]-2,4-thiazolidinediones and [[(heterocyclylamino)alkoxy]benzyl]-2,4-thiazolidinediones was synthesized from the corresponding aldehydes. Compds. from the urea series, exemplified by I, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045). The benzoxazole II, a cyclic analog of I, was a very potent enhancer of insulin sensitivity, and by modification of the arom. heterocycle, an aminopyridine, III, was identified as a lead compd. from SAR studies. Evaluation of antihyperglycemic activity together with effects on blood Hb content, to det. the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 B1/6 ob/ob mice. From these studies, III (BRL 49653) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against redns. in blood Hb content, for further evaluation.
Original languageEnglish
Pages (from-to)3977-3985
Number of pages9
JournalJournal of Medicinal Chemistry
Volume37(23)
Publication statusPublished - 1994

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