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Repaglinide and related hypoglycemic benzoic acid derivatives
1Departments of Chemical and Biological Research, Boehringer Ingelheim Pharma KG, Postfach 1755, D-88397 Biberach, Germany.
Journal of Medicinal Chemistry
|December 19, 1998
Summary
Researchers investigated hypoglycemic benzoic acid derivatives, identifying repaglinide as a potent therapeutic for type 2 diabetes. This new compound exhibits significantly higher activity than existing sulfonylureas, offering a promising treatment option.
Area of Science:
- Medicinal Chemistry
- Pharmacology
Background:
- Hypoglycemic benzoic acid derivatives are explored for type 2 diabetes treatment.
- Meglitinide analogs serve as a basis for developing new antidiabetic agents.
Purpose of the Study:
- To investigate structure-activity relationships in two series of hypoglycemic benzoic acid derivatives.
- To identify novel compounds with enhanced hypoglycemic activity compared to existing drugs.
Main Methods:
- Synthesis and evaluation of two series of benzoic acid derivatives (5 and 6).
- Comparative activity assessment against glibenclamide and glimepiride in rats.
- Pharmacophore modeling and analysis of low-energy conformations.
Main Results:
- The most active compounds in series 5 featured cis-3, 5-dimethyl-piperidino and octamethyleneimino residues.
- Compound 6al, with an ethoxy group, showed 12 times higher activity than glibenclamide and was predominantly active in its (S)-enantiomer.
- (S)-repaglinide demonstrated 25 and 18 times greater potency than glibenclamide and glimepiride, respectively.
Conclusions:
- A third pharmacophoric group (ortho residue R1) was identified for hypoglycemic benzoic acid derivatives.
- A common binding conformation may exist for benzoic acid derivatives and sulfonylureas.
- Repaglinide is a valuable therapeutic for type 2 diabetes, recently approved by FDA and EMEA.