Retrometabolic approaches are novel systematic methodologies aimed to improve the therapeutic index that thoroughly integrate structure-activity and structure-metabolism relationships in the drug design process. The particular advantage of these approaches is to enhance, sometimes very significantly, drug targeting to the site of action. They include two distinct approaches to design soft drugs and chemical delivery systems (CDS), respectively. Soft drugs and chemical delivery systems are opposite in terms of how they achieve their drug targeting role, but they have in common the basic concept of designed metabolism to control drug action and targeting. For CDSs, the molecule is designed to be inactive and to undergo strategic enzymatic activation in order to release the active agent only at the site of action. Delivery of this kind was successfully achieved to the brain, to the eye, and to other organs such as lungs. On the other hand, soft drugs are intrinsically potent new drugs that are strategically deactivated after they achieve their therapeutic role. These approaches are general in nature, and can be applied to essentially all drug classes. A number of specific examples (i.e., soft anticholinergics, soft corticosteroids, and kyotorphin-CDS) were included to illustrate these design principles. Computational techniques that help in the generation, ranking, or evaluation of the new drug candidates are also reviewed. The main focus in the development of these computational techniques was to provide a reliable theoretical method that can evaluate the systems of interest before experimental work is performed in order to minimize the time and expense of random laboratory testing and evaluation. Cyclodextrins proved useful in improving the solubility and stability properties of these CDSs; a number of related recent theoretical studies are also summarized.
|Translated title of the contribution||Retrometabolic drug design: Principles, examples, and computational techniques|
|Number of pages||6|
|Journal||Magyar Kemiai Folyoirat, Kemiai Kozlemenyek|
|State||Published - Dec 1 1999|
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