Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl)propanamides as glucokinase activators

Fuying Li, Qingzhang Zhu, Yi Zhang, Ying Feng, Ying Leng, Ao Zhang

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

A series of N-thiazole substituted arylacetamides were designed on the basis of metabolic mechanism of the aminothiazole fragment as glucokinase (GK) activators for the treatment of type 2 diabetes. Instead of introducing a substituent to block the metabolic sensitive C-5 position on the thiazole core directly, a wide variety of C-4 or both C-4 and C-5 substitutions were explored. Compound R-9k bearing an iso-propyl group as the C-4 substituent was found possessing the highest GK activation potency with an EC50 of 0.026 μM. This compound significantly increased both glucose uptake and glycogen synthesis in rat primary cultured hepatocytes. Moreover, single oral administration of compound R-9k exerted significant reduction of blood glucose levels in both ICR and ob/ob mice. These promising results indicated that compound R-9k is a potent orally active GK activator, and is warranted for further investigation as a new anti-diabetic treatment.

Original languageEnglish (US)
Pages (from-to)3875-3884
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number11
DOIs
StatePublished - Jun 1 2010
Externally publishedYes

Keywords

  • Aminothiazole
  • Arylacetamide
  • Glucokinase activator
  • Type 2 diabetes (T2D)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl)propanamides as glucokinase activators'. Together they form a unique fingerprint.

Cite this