Retrometabolism‐Based Drug Design and Targeting

Abstract

Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

Design, Synthesis, and Biological Evaluation of Novel, Highly Active Soft ROCK Inhibitors

“…Reversal of the amide linker resulted in increased activity but also in increased stability (6 vs 17; 13 vs 19). The latter could again be easily varied by changing the ester chain (18,20). Fluorine atoms allowed At this point, we sought to experimentally verify the binding mode of soft ROCK inhibitors in ROCK to provide further rationale for the observed SAR and additional insights regarding compound optimization.…”

Soft Glucocorticoids: Eye-Targeted Chemical Delivery Systems (CDSs) and Retrometabolic Drug Design: A Review

“…In an effort to minimize ADRs and other complicacies associated with glucocorticoids, Bodor and his colleagues for the first time have developed the concept of retrometabolic drug design for ophthalmic therapeutics to introduce a new and unique class of glucocorticoids now known as soft corticosteroids or soft glucocorticoids that helped in developing glucocorticoid soft drugs for ophthalmic use [24,[48][49][50]. Soft -blockers are also falling in this soft drug category.…”

“…Soft -blockers are also falling in this soft drug category. The concept of soft drugs has been originated from the pioneer work of Prof. N Bodor and his co-workers at the Center for Drug Discovery, University of Florida, Health Science Center, Gainesville, FL 32610-0497, USA [24,[48][49][50]. The possibility of developing these soft drugs has been extensively studied along the lines of retro-metabolic drug design for two important classes of ophthalmic drugs, -blockers and glucocorticoids [24].…”

“…The inactive metabolite is then converted to an isosteric or isoelectronic analog with structural modifications designed for a rapid and predictable metabolism back to the original inactive metabolite after exerting the desired therapeutic effect at the site (Figure 2) [24,26]. These analogs or soft drugs were predicted to have therapeutic potential similar to that of the lead compound, but because of the structural modifications provided by the design, any active drug remaining after attainment of the therapeutic effect would be metabolically deactivated, thus reducing adverse drug reactions (ADRs) [24,26,[48][49][50][51]. According to Prof Bodor, in developing soft drugs the goal is not to avoid metabolism but rather to control and direct it.…”

Synthesis and Evaluation of PPARδ Agonists That Promote Osteogenesis in a Human Mesenchymal Stem Cell Culture and in a Mouse Model of Human Osteoporosis

“…10 h in rats and nearly double that in humans, but its detailed disposition has not been fully reported, in particular, with regard to the possibility that it could produce low levels of localized toxic metabolites that become insidious upon long-term dosing. A composite of metabolic possibilities for PPARδ ligands is summarized in Figure A. , By analogy to other agents, cardarine’s aryl-thioether, head-core-linkage region resides in a metabolic soft spot , such that the aryl moiety may be susceptible to CYP-450-mediated aromatic hydroxylation, whereas the sulfur may be subject to CYP-450-mediated S-dealkylation and to CYP-450 or flavin-containing monooxygenase (FMO)-mediated S-oxidation . The latter can complicate PK profiling because the S atom becomes asymmetric, whereas the dealkylated metabolite could contribute to toxicity because of the resulting aryl-sulfhydryl group’s inherent reactivity .…”