Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones as antihyperglycemic agents

Journal of Medicinal Chemistry
J WrobelD Sullivan

Abstract

Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the 3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear, although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good potency. Several compounds from series 2 were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese, insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.

Citations

Jul 29, 2000·Bioorganic & Medicinal Chemistry Letters·J WrobelD Sullivan
May 2, 2002·Bioorganic & Medicinal Chemistry·V Sreenivasa Murthy, Vithal M Kulkarni
Feb 28, 2001·Diabetes, Obesity & Metabolism·M J Reed, K A Scribner
Jul 7, 2005·Antioxidants & Redox Signaling·Joseph L EvansIra D Goldfine
Mar 25, 2005·Organic Letters·Ma Carmen Pacheco, Véronique Gouverneur

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