Rabbit corneal and conjunctival permeability of the novel aldose reductaseinhibitors: N-{[4-(benzoylamino)phenyl] sulphonyl} glycines and N-benzoyl-N-phenylglycines

Corneal and conjunctival permeability has been investigated for novel aldos e reductase inhibitors (ARIs) of the N{[4-(benzoylamino)phenyl]sulphonyl}gl ycine (benzoylaminophenylsulphonylglycine) and N-benzoyl-N-phenylglycine (b enzoylphenylglycine) series, compounds developed for prevention of cataract formation in diabetic subjects. Six benzoylaminophenylsulphonylglycines were synthesized with modifications either of the phenyl group or of the glycine structure and three benzoylph enylglycines were synthesized with modification in the phenyl group of the benzoyl moiety. Transport of ARIs in the mucosal to serosal direction was e valuated across rabbit cornea and conjunctiva bathed in glutathione-bicarbo nate Ringer's solution maintained at pH 7.4 and 37 degrees C. The permeabil ity coefficients of the novel ARIs across cornea and conjunctiva ranged fro m 1.87 to 8.95 x 10(-6) cm s(-1) and from 4.6 to 19.15 x 10(-6) cm s(-1), r espectively. The ratio of corneal to conjunctival permeability ranged from 0.12 to 0.79. The calculated log partition coefficient (log P) values for t he ARIs were in the range 0.84 to 2.78. The log distribution coefficients ( log D) were in the range -2.87 to -0.89. There was no apparent relationship between log P or log D and the permeability coefficients of the ARIs for e ither tissue. Cornea was more resistant to ARI transport than was conjuncti va. Substitution of a phenyl group for hydrogen in the glycine methylene gr oup reduced the permeability coefficient. Permeability coefficients were di fferent for different stereoisomers. Compared with the permeability coeffic ient of benzoylaminophenylsulphonylglycine, that of 4-fluorobenzoylaminophe nylsulphonylglycine was lower in the cornea but similar in the conjunctiva. In both tissues, the permeability coefficient of 2-nitrobenzoylaminophenyl sulphonylglycine was less than that of 4-nitrobenzoylaminophenylsulphonylgl ycine. There was no significant difference between the permeability coeffic ients of 3-nitro- and 4-nitrobenzoylphenylglycines through either tissue an d the permeability coefficients of these compounds were greater than that o f the more lipophilic 4-methylbenzoylphenylglycine. The lack of dependence of the permeability coefficients on log P or log D a nd the different permeabilities of stereoisomers imply the existence of spe cialized transport processes for the ARIs tested in this study.