Soft drug design: General principles and recent applications

Abstract

Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, β‐blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 1, 58–101, 2000.

Novel approaches on prodrug based drug design

“…This review is intended to focus on the recent advances in the applications of the prodrug concept. This include gene directed and antibody-directed enzyme prodrug therapy, a number of specific organ-targeted delivery systems, nucleoside and nucleotide prodrugs, in addition to recent developments in steroidal anti-inflammatory prodrugs, mutual prodrugs, macromolecular prodrugs, and a few examples of a related class of drugs developed by Bodor called soft-drugs [3]. Bodor defined soft-drugs as 'biologically active, therapeutically useful chemical compounds characterized by a predictable and controllable metabolism to non-toxic moieties, after they have achieved their therapeutic role.…”

Effects of Topical Loteprednol Etabonate on Tear Cytokines and Clinical Outcomes in Moderate and Severe Meibomian Gland Dysfunction: Randomized Clinical Trial

“…15,16 Loteprednol etabonate, a novel C 20 ester-based corticosteroid, was retrometabolically designed to provide potent anti-inflammatory efficacy, but with decreased impact on intraocular pressure (IOP). 17 After exerting its therapeutic effects at the site of action, it is rapidly converted to inactive metabolites, thereby resulting in fewer adverse effects. 17 Several clinical studies evaluating the efficacy of 0.5% loteprednol etabonate ophthalmic suspension (Lotemax; Bausch and Lomb Inc, Rochester, New York, USA) in patients with acute anterior uveitis, giant papillary conjunctivitis, seasonal allergic conjunctivitis, postoperative inflammation, and ocular pain showed efficacy of this medication.…”

Hierarchical QSAR technology based on the Simplex representation of molecular structure

“…Some molecular fragments promoting and interfering anti-influenza activity [12,30,42] are represented in Table 1 as well as their average relative influence on it. Based on the SiRMS, it is possible to realize the molecular design of compounds with the desired activity level via the generation of allowed combinations of simplexes determining the property being investigated. The simplest way is the soft drug design [43] that consists of replacing undesired fragments by more active ones, or by the insertion of fragments promoting the activity at positions of indifferent parts of the molecule or hydrogen atoms. The usage of this technique allows the design of new compounds at the same region of structural space as the training set of compounds.…”