Diabetes is a frequently cited risk factor in cataract generation. During diabetes, formation and accumulation of polyols have been implicated in the etiology of sugar cataract in animal models as well as humans. Aldose reductase, an enzyme present in the lens and other tissues is responsible for polyol synthesis under hyperglycemic conditions. Aldose reductase inhibitors (ARIs) were shown to prevent cataract formation in several animal models. These agents are also of use as an intervention therapy, if used at an early stage following onset of diabetes. Several different chemical moieties have exhibited inhibitory activity against aldose reductase. Of several chemical entities synthesized by our group, N-[4-(benzoylamino)phenylsulfonyl] amino acids (BAPSAAs) and isosteric N-benzoyl N-phenyl glycines (Bz-N- PhGs) displayed the highest degree of ARI activity. Although prevention of cataract by ARIs following topical administration has been reported, majority of studies conducted thus far administered ARIs orally. The objective of this study is to test the hypothesis that ocular administration, in addition to providing high drug levels in the lens, will also provide adequate systemic levels following topical administration. This study will evaluate the systemic and ocular delivery of novel ARIs synthesized by our group and further evaluate the use of selected ARIs in cataract therapy.
The specific aims of the current study are: (1) to identify an ARI with optimal activity and corneal permeability and to synthesize, purify, and characterize the physicochemical properties of a series of lipophilic prodrugs of the chosen novel ARI, (2) to evaluate the chemical and enzymatic hydrolysis of these prodrugs and to evaluate their in vitro activity, (3) to evaluate the in vitro transport and the ocular tissue uptake and systemic bioavailability of the prodrugs following topical administration to rabbits, and (4) to determine the usefulness of prodrugs with optimal pharmacokinetic properties as preventive and intervention therapeutic agents for cataract. The project will employ chemical synthesis, pharmaceutical analysis, chemical stability, enzyme kinetics, and pharmacokinetic studies. The importance of this work is that it will set stage for evaluating the utility of ocularly administered novel ARIs and their prodrugs in alleviating diabetic complications in the eye as well as the system.
