Topical Carbonic Anhydrase Inhibitors III: Optimization Model for Corneal Penetration of Ethoxzolamide Analogues

An analogue series representing modification to the benzene ring of ethoxzolamide has been evaluated for solubility, pKa, partitioning, and permeability across excised rabbit corneas. These physical parameters were correlated to Hammett σ (para) and/or Hansch π parameter values for each compound. From these correlations, a mathematical model was developed relating corneal permeability to molecular modifications of ethoxzolamide. A three‐dimensional plot of maximium attainable penetration rate versus σ (para) and π yielded an optimal range of π and σ values from which an optimally penetrating analogue could be designed.