NOVEL CAI DERIVATIVES FOR TOPICAL APPLICATION

IN MORE THAN 50% OF GLAUCOMA PATIENTS INTRAOCULAR PRESSURE (IOP) IS NOT ADEQUATELY CONTROLLED BY SINGLE DRUG THERAPY. OPTIC NERVE DAMAGE ASSOCIATED WITH ELEVATED IOP IS THE LEADING CAUSE OF IRREVERSIBLE BLINDNESS IN THE WESTERN WORLD. THE DEVELOPMENT OF ADDITIONAL DRUGS TO TREAT GLAUCOMA EITHER ALONE OR IN COMBINATION WITH CURRENTLY AVAILABLE MEDICATIONS SUCH AS THE ADRENERGIC A-ANTAGONISTS THEREFORE IS APPROPRIATE. THE DEVELOPMENT OF NOVEL DERIVATIVES AND ANALOGS OF THE CARBONIC ANHYDRASE INHIBITOR (CAI) ACETAZOLAMIDE IS THE AIM. CURRENTLY CAI'S SUCH AS ACETAZOLAMIDE ARE ADMINISTERED ORALLY TO LOWER IOP. THE ORAL ROUTE OF ADMINISTRATION UNFORTUNATELY CAUSES MANY UNDESIRABLE SIDE EFFECTS. THE NEW COMPOUNDS ARE EXPECTED TO LOWER IOP WHEN APPLIED TOPICALLY, AS DRUG ACTIVITY WILL BE LOCALIZED IN THE EYE. THUS SIDE EFFECTS COMMONLY ASSOCIATED WITH THE USE OF CAI'S WILL BE AVOIDED. THE RESEARCH WILL INVOLVE THE SYNTHESIS OF SIX NOVEL COMPOUNDS. IN VITRO ACTIVITY STUDIES WILL EVALUATE CARBONIC ANHYDRASE INHIBITION BY THE COMPOUNDS. PERMEABILITY ACROSS RABBIT CORNEA WILL BE DETERMINED. THE PHASE I STUDY WILL PROVIDE A STRONG FOUNDATION FOR FURTHER DEVELOPMENT IN PHASE II. BENEFITS OF THE NEW DRUGS INCLUDE IMPROVED BIOAVAILABILITY, FEWER SIDE EFFECTS AND THEREFORE IMPROVED PATIENT COMPLIANCE.