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, ␤-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.

Topical Corticosteroids and Antihistamines—Mast Cell Stabilizers for the Treatment of Allergic Conjunctivitis

“…after eliciting the desired therapeutic effect, this analog undergoes rapid, predictable metabolism back to the original inactive metabolite. 62 Because of this retrometabolic design, le has several advantages over the c-20 ketone-based corticosteroids.…”

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

“…Soft corticosteroids or Soft glucocorticoids can be termed as a unique class of new generation glucocorticoids that are designed specifically for ophthalmic therapeutics [24][25][26][27]. The new generation glucocorticoids developed by prodrug approach as described earlier have brought revolution in treating a plethora of disease including psoriasis, allergies, asthma, rheumatoid arthritis and lupus because of their minimized systemic side effects.…”

“…Chemical Delivery Systems (CDSs) and Retrometabolic drug design principles have led to development of a new but unique class of glucocorticoids which are safe and effective in treating a wide variety of ocular inflammatory conditions including giant papillary conjunctivitis, seasonal allergic conjunctivitis, and uveities as well as in the treatment of ocular inflammation and pain following cataract surgery. This new and unique class of glucocorticoids are now known as soft glucocorticoids which are associated with highly minimized ADRs to justify terming them as `soft drugs' [24,26].…”

Carboxylesterases from the seeds of an underutilized legume, Mucuna pruriens; isolation, purification and characterization

“…Carboxylesterase activity is also used extensively in soft-and pro-drug design (Bodor and Buchwald, 2000, 2003. However, the natural substrates for the majority of carboxylesterases remain unknown, the activity being characterized using synthetic substrates, such as a-or b-naphthyl esters and p-nitrophenyl esters (Dubey et al, 2000).…”