Structure
Tolbutamide is a first-generation sulfonylurea with a benzene ring substituted with a sulfonylurea moiety and butyl side chains.
Chemical Formula: C₁₆H₂₅N₃O₃S
Mode of Action
ATP-Sensitive K⁺ Channel Blockade: Inhibits K⁺ channels on pancreatic beta cells, leading to cell membrane depolarization.
Calcium Influx: Depolarization opens voltage-dependent calcium channels, increasing intracellular calcium.
Insulin Secretion: Elevated calcium stimulates insulin granule exocytosis, enhancing insulin release.
Uses
Type 2 Diabetes Mellitus: Improves glycemic control by increasing insulin secretion.
Gestational Diabetes: Used cautiously under medical supervision to manage blood glucose levels.
Structure-Activity Relationship (SAR)
Sulfonylurea Moiety: Essential for binding to the SUR1 (sulfonylurea receptor 1) subunit of the K⁺ channel.
Alkyl Side Chains: Longer butyl chains enhance lipophilicity and binding affinity.
Benzene Substitution: Substituents on the benzene ring can affect potency and duration of action.
Synthesis
Tolbutamide is synthesized through the reaction of 2,4-diethylbenzenesulfonyl chloride with urea, followed by condensation with N,N-dimethylurea.
Synthetic Route Overview:
2,4-Diethylbenzenesulfonyl chloride + Urea → Tolbutamide