Rabbit Corneal and Conjunctival Permeability of the Novel Aldose Reductase Inhibitors: N-{[4-(Benzoylamino)phenyl] sulphonyl}glycines and N-Benzoyl-N-phenylglycines

Abstract

Corneal and conjunctival permeability has been investigated for novel aldose reductase inhibitors (ARIs) of the N{[4-(benzoylamino)phenyl]sulphonyl}glycine (benzoylaminophenylsulphonylglycine) and N-benzoyl-N-phenylglycine (benzoylphenylglycine) 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 benzoylphenylglycines were synthesized with modification in the phenyl group of the benzoyl moiety. Transport of ARIs in the mucosal to serosal direction was evaluated across rabbit cornea and conjunctiva bathed in glutathione-bicarbonate Ringer's solution maintained at pH 7.4 and 37 degrees C. The permeability coefficients of the novel ARIs across cornea and conjunctiva ranged from 1.87 to 8.95 x 10(-6) cm s(-1) and from 4.6 to 19.15 x 10(-6) cm s(-1), respectively. The ratio of corneal to conjunctival permeability ranged from 0.12 to 0.79. The calculated log partition coefficient (log P) values for the 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 either tissue. Cornea was more resistant to ARI transport than was conjunctiva. Substitution of a phenyl group for hydrogen in the glycine methylene group reduced the permeability coefficient. Permeability coefficients were different for different stereoisomers. Compared with the permeability coefficient of benzoylaminophenylsulphonylglycine, that of 4-fluorobenzoylaminophenylsulphonylglycine was lower in the cornea but similar in the conjunctiva. In both tissues, the permeability coefficient of 2-nitrobenzoylaminophenylsulphonylglycine was less than that of 4-nitrobenzoylaminophenylsulphonylglycine. There was no significant difference between the permeability coefficients of 3-nitro- and 4-nitrobenzoylphenylglycines through either tissue and the permeability coefficients of these compounds were greater than that of the more lipophilic 4-methylbenzoylphenylglycine. The lack of dependence of the permeability coefficients on log P or log D and the different permeabilities of stereoisomers imply the existence of specialized transport processes for the ARIs tested in this study.

Recent advances in aldose reductase inhibitors: potential agents for the treatment of diabetic complications

“…The compound was found to lower plasma triglycerides in diabetic rats by 68% at a dose of 10 mg/kg/day, to reduce blood glucose in diabetic mice at 100 mg/kg/day and to inhibit angiogenesis. Benzoylaminophenylsulfonylglycine (23) and benzoylphenylglycine (24) have been reported to possess AR inhibitory activity with IC 50 values of 0.4 and 0.25 µM, respectively [45,46]. The former could be seen as a bioisoster of a phenylsulfonylnitromethane.…”

Formal C–H/C–I Metathesis: Site-Selective C–H Iodination of Anilines Using Aryl Iodides

“…Recently, we achieved the meta - and ortho- C–H iodination of hydrocinnamic acids using 2-nitrophenyl iodides as very mild iodinating reagents via a rare formal C–H/C–I metathesis through the selective reductive elimination of C­(sp 2 )–I over C­(sp 2 )–C­(sp 2 ) . Since these reagents are very mild and not electrophilic, we envisioned that they could be applied for the meta -C–H iodination of electron-rich substrates such as anilines, which turned out to be feasible after our intense study based on our previous carboxyl-assisted meta -C–H activation of arenes. , Meanwhile, the ortho -C–H iodination of anilines was also investigated, since N -acetyl- N -arylglycines are biologically active aldose reductase inhibitors . Herein, we report methods for the meta - and ortho- C–H iodination of aniline derivatives via formal C­(sp 2 )–H/C­(sp 2 )–I metathesis using 2-nitrophenyl iodides as the iodinating reagents (Scheme b). − …”