Syntheses of substituted 2,4-dioxo-thienopyrimidin-1-acetic acids and their evaluation as aldose reductase inhibitors

K. Ogawva, I. Yamawaki, YI Matsusita, N. Nomura, PF Kador, JH Kinoshita

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

A series of 2,4-dioxo-thieno[2,3-d], [3,2-d] and [3,4-d]pyrimidin-1-acetic acids (2) with a benzyl moiety at the N-3 position were prepared and tested in vitro for aldose reductase inhibitory activity against partially purified enzyme from rat lens. Some of these compounds were also evaluated for inhibition of sorbitol accumulation in the sciatic nerve or lens of streptozotocin-induced diabetic rats in vivo. Among the synthesized compounds, several showed potent aldose reductase inhibitory activity with IC50s in the 10-8 M range. Particularly, the potencies of non-substituted thieno- (2a and 2aa), 5-methylthieno- (2c), 5,6-dimethylthieno-(2g), 6-isopropylthieno- (2j and 2k), 6-chlorothienopyrimidine (2q) and benzothienopyrimidine (2ac) analogs were approximately equipotent to FK-366 (1A) and Ponalrestat (1B) as references. Although most compounds were inactive in vivo, 2 compounds, 2k and 2q, possessed moderate in vivo activity.

Original languageEnglish (US)
Pages (from-to)769-781
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume28
Issue number10
DOIs
StatePublished - 1993

Keywords

  • 2,4-dioxo-thieno[2,3-d][3,2-d]
  • [3,4-d]pyrimidin-1-acetic acids
  • aldose reductase inhibitory activity
  • sorbitol accumulation inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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