Soft drug inactive metabolite

The soft drug concept was introduced in 1976 [24] and reiterated in 1980 [30-32], Since then, five distinct types have been identified [21, 25, 27-29, 33] (1) soft analogues, (2) soft drugs based on the inactive metabolite approach, (3)... 

Synthesis of the soft drug , loteprednol etabonate, was achieved by starting with a known inactive metabolite of a known active dmg. The inactive metabolite was then modified to an active form which, after having achieved its therapeutic role, was subsequently metabolized to an inactive species. 

Soft -blockers. Because in this class inactive metabolite-based soft drugs can be obtained by introducing the hydrolytically sensitive functionality at a flexible pharmacophore region, there is considerable freedom for structural modifications. Consequently, transport and metabolism properties can be controlled more easily. 

F igure 15.4. Comparison of the metabolism of metoprolol (3) with that of the soft drugs (8)designed starting from one of its inactive metabolites (7).The dashed line in structures (8)and (9)denotesthe possibility of having either isopropyl- or iert-butyl-substituted amines. 

A hypothetical inactive metabolite-based soft drug approach proved useful in solving these problems. A first attempt to incorporate ester and carbonate moieties into structure (21) (Fig. 15.8) at the R, side-chain (R2 = —CHgOgCR, —CHgOgCOR ) produced potent analgetics, but durations of action were... 

Currently, it is the only corticosteroid approved by the FDA for use in all inflammatory and allergy-related ophthalmic disorders, including inflammation after cataract surgery, uveitis, allergic conjunctivitis, and giant papillary conjunctivitis. Loteprednol etabonate resulted from a classic inactive metabolite-based soft drug approach (103-114). 

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