Retrometabolic drug design

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).

Since its introduction by Nicholas Bodor in the late 1970s, the soft drug concept generated considerable research both in academic and in industrial settings.

Within this approach, three major general CDS classes have been identified: 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[26][27][28] in 1975, 1981 and 1983.

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.

Loteprednol etabonate, a soft corticosteroid designed and patented[36][37] by Bodor received final Food and Drug Administration (FDA) approval in 1998 as the active ingredient of two ophthalmic preparations (Lotemax and Alrex), currently the only corticosteroid approved by the FDA for use in all inflammatory and allergy-related ophthalmic disorders.

Its safety for long-term use[38] further supports the soft drug concept, and in 2004, loteprednol etabonate[39][40][41] was also approved as part of a combination product (Zylet).

A second generation of soft corticosteroids such as etiprednol dicloacetate[42] is in development for a full spectrum of other possible applications such as nasal spray for rhinitis or inhalation products for asthma.

Following the introduction of the CDS concepts, work along those lines started in numerous pharmaceutical centers around the world, and brain-targeting CDSs were explored for many therapeutic agents such as steroids (testosterone, progestins, estradiol, dexamethasone), anti-infective agents (penicillins, sulfonamides), antivirals (acyclovir, trifluorothymidine, ribavirin), antiretrovirals (AZT, ganciclovir), anticancer agents (Lomustine, chlorambucil), neurotransmitters (dopamine, GABA), nerve growth factor (NGF) inducers, anticonvulsants (Phenytoin, valproate, stiripentol), Ca2+ antagonists (felodipine), MAO inhibitors, NSAIDs and neuropeptides (tryptophan, Leu-enkephalin analogs, TRH analogs, kyotorphin analogs).