Retrometabolic drug design

The concept of retrometabolic drug design encompasses two distinct approaches. One approach is the design of soft drugs (SDs), new, active therapeutic agents, often isosteric or isolelectronic analogs of a lead compound, with a chemical structure specifically designed to allow predictable metabolism into inactive metabolites after exerting their desired therapeutic effect(s). The other approach is the design of chemical delivery systems (CDSs). CDSs are biologically inert molecules intended to enhance drug delivery to a particular organ or site and requiring several conversion steps before releasing the active drug. Although both retrometabolic design approaches involve chemical modifications of the molecular structure and both require enzymatic reactions to fulfill drug targeting, the principles of SD and CDS design are distinctly different. While CDSs are inactive as administered and sequential enzymatic reactions provide the differential distribution and ultimately release the active drug, SDs are active as administered and are designed to be easily metabolized into inactive species. Assuming an ideal situation, with a CDS the drug is present at the site and nowhere else in the body because enzymatic processes destroy the drug at those sites. Whereas, CDSs are designed to achieve drug targeting at a selected organ or site, SDs are designed to afford a differential distribution that can be regarded as reverse targeting. Soft drugs Since its introduction by Nicholas Bodor in the late 1970s, the soft drug concept generated considerable research both in academic and in industrial settings. Bodor defined soft drugs as biologically active, therapeutically useful chemical compounds characterized by a predictable and controllable in vivo metabolism to non-toxic moieties after they achieve their therapeutic role. There are several rationally designed soft drugs that have either already reached the market, such as • esmolol (Breviblock) • landiolol (Onoact) • remifentanil (Ultiva) • loteprednol etabonate (Lotemax, Alrex, Zylet) • clevidipine (Cleviprex) • remimazolam (Byfavo) or are in late-stage development (budiodarone, celivarone, AZD3043, tecafarin). There are also compounds that can be considered as soft chemicals (e.g., malathion) or soft drugs (e.g., articaine, methylphenidate) even though they were not developed as such. in 1975, 1981 and 1983. Its extension to the targeted brain-delivery of neuropeptides was included by the Harvard Health Letter as one of the top 10 medical advances of 1992. Several compounds have reached advanced clinical development phase, such as :* E2-CDS (Estredox) for the brain-targeted delivery of estradiol and :* betaxoxime for the eye-targeted delivery of betaxolol In the first example above, brain-targeted CDSs employ a sequential metabolic conversion of a redox-based targetor moiety, which is closely related to the ubiquitous NAD(P)H ⇌ NAD(P)+ coenzyme system, to exploit the unique properties of the blood–brain barrier (BBB). After enzymatic oxidation of the NADH type drug conjugate to its corresponding NAD+- drug, the still inactive precursor, "locks-in" behind the BBB to provide targeted and sustained CNS-delivery of the compound of interest. The second example involves eye-specific delivery of betaxoxime, the oxime derivative of betaxolol. The administered, inactive β-amino-ketoxime is converted to the corresponding ketone via oxime hydrolase, an enzyme recently identified with preferential activity in the eye, and then stereospecifically reduced to its alcohol form. IOP-lowering activity is demonstrated without producing the active β-blockers systemically, making them void of any cardiovascular activity, a major drawback of classical antiglaucoma agents. Because of the advantages provided by this unique eye-targeting profile, oxime-based eye-targeting CDSs could replace the β-blockers currently used for ophthalmic applications. == History and significance ==