In the field of drug discovery, retrometabolic drug design is a strategy for the design of safer drugs either using predictable metabolism to an inactive moiety or using targeted drug delivery approaches. The phrase retrometabolic drug design was coined by Nicholas Bodor. The method is analogous to retrosynthetic analysis where the synthesis of a target molecule is planned backwards. In retrometabolic drug design, metabolic reaction information of drugs is used to design parent drugs whose metabolism and distribution can be controlled to target and eliminate the drug to increase efficacy and minimize undesirable side effects. The new drugs thus designed achieve selective organ and/or therapeutic site drug targeting and produce safe therapeutic agents and safe environmental chemicals. These approaches represent systematic methodologies that thoroughly integrate structure-activity (SAR) and structure-metabolism (SMR) relationships and are aimed at designing safe, locally active compounds with improved therapeutic index (ratio of benefit vs. side effect).
Classification 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.
Chemical delivery systems Since their introduction in the early 1980s, CDSs have also generated considerable research work, especially for brain and eye targeting of various therapeutic agents, including those that cannot cross the blood–brain barrier or the blood–retinal barrier on their own. Within this approach, three major general CDS classes have been identified:
Enzymatic physicochemical-based (e.g., brain-targeting) CDSs: exploit site-specific traffic properties by sequential metabolic conversions that result in considerably altered properties Site-specific enzyme-activated (e.g., eye-targeting) CDSs: exploit specific enzymes found primarily, exclusively, or at higher activity at the site of action Receptor-based transient anchor-type (e.g., lung-targeting) CDSs: provide enhanced selectivity and activity through transient, reversible binding at the receptor This concept has been extended to many drugs and peptides, its importance illustrated by the fact that its first applications and uses were published in Science 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.
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