RETROMETABOLIC DRUG DESIGN CONCEPTS IN OPHTHALMIC TARGET-SPECIFIC DRUG-DELIVERY

Most ophthalmic drugs were not developed originally for the treatment of eye diseases. The specific anatomical, biochemical and transport, enzymatic features of the eye have to be taken into account to successfully design safer specific ophthalmic drugs. Two major novel metabolism-based drug design concepts were developed, which have significant advantages when used in the design of specific ophthalmic drugs. One approach is based an predictable enzymatic activation processes by enzymes found primarily, exclusively or at higher activity at the site of action - in this case within the eye, primarily in the iris-ciliary body. This is called the chemical delivery systems (CDS) approach. This approach involves designing an inactive chemical precursor of an active drug, which is then activated within the eye and only within the eye. An example is given by site and stereospecific enzymatic sequential activation of oxime/alkoxime precursors of beta-adrenergic antagonists. The second major retrometabolic design technique involves soft drug approaches. Among the various soft design strategies, the 'inactive metabolite' and the 'soft analog' approaches prove to be most useful to design safe and selective ophthalmic drugs. Accordingly, the design process starts from a known inactive metabolite (M(i)) of the drug (D). This M(i) is structurally modified to provide the soft drug (SD), which is isosteric and/or isoelectronic with (D). Accordingly, it provides good receptor binding properties and it is an active analog of (D). However, by design, SD is subject to a facile, predictable (generally hydrolytic) metabolism, leading in one step to its deactivation to the original inactive Mi. As this deactivation takes place everywhere in the body, the desired activities are produced exclusively at the target site at or near the application. This approach is exemplified by soft beta-blocker design, which clearly shows the design principles opposite to the CDS approach; soft anticholinergics for short mydriatic-cycloplegic activity; and soft corticosteroids which have the major benefit of providing good anti-inflammatory activity in the eye but essentially lack side effects like elevation of intraocular pressure or cataract formation. These concepts and approaches are general in nature and are possible to apply to design of various novel and safe ophthalmic drugs.