Prodrug Design to Improve Pharmacokinetic and Drug Delivery Properties: Challenges to the Discovery Scientists
Abstract:The prodrug design is a versatile, powerful method that can be applied to a wide range of parent drug molecules, administration routes, and formulations. Clinically, the majority of prodrugs are used with the aim of enhancing drug permeation by increasing lipophilicity, or by improving aqueous solubility. Prodrug design may improve the bioavailability of parent molecule, and thus can be integrated into the iterative process of lead optimization, rather than employing it as a post-hoc approach. The purpose of this review is to provide an update of advances and progress in the knowledge of current strategic approaches of prodrug design, along with their real-world utility in drug discovery and development. The review covers the type of prodrugs and functional groups that are amenable to prodrug design. Various prodrug approaches for improving oral drug delivery are discussed, with numerous examples of marketed prodrugs, including improved aqueous solubility, improved lipophilicity, transporter-mediated absorption, and prodrug design to achieve site-specific delivery. Tools employed for prodrug screening, and specific challenges in prodrug research and development are also elaborated. This article is intended to encourage discovery scientists to be creative and consider a rationally designed prodrug approach during the lead optimization phase of drug discovery programs, when the structure activity relationship (SAR) for the drug target is incompatible with pharmacokinetic or biopharmaceutical objectives.
Keywords: 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA); Absorption; Acyclovir; Acyloxyalkyl Prodrugs; Bioprecursor; Bopindolol; Caco-2; Capecitabine; Carbamate Prodrugs; Carrier-linked prodrugs; Chemical delivey System (CDS); Dipivefrine; Docarpamine; Enalapril; Gabapentin; Gancyclovir; Glaucoma; Hepatic clearance; Losartan; Lovastatin; Melevodapa; Mestranol; Nitazoxamide; Nitroreductase; Oxidative; P-glycoprotein; Phosphate Ester Prodrugs; Quinapril; Schiff Base Prodrugs; Simvastatin; Spirapril; Sulfasalazine; Sulindac; Terfenadine; Tumour Targeting; Viramidine; adefovir dipivoxil; angiotensin-converting enzyme (ACE); antibody-directed enzyme prodrug therapy (ADEPT); antimicrobial prodrugs; antiparasitic; antiproliferative agent; antitubercular; bacampicillin; bambuterol; bioavailability; blood-brain barrier; carrier-mediated transport; colonic mucosa; cyclophosphamide; cytotoxic agents; desglymidodrine; distribution, metabolism, and excretion (ADME); drug targeting; enterocyte; fosphenytoin; gene-directed enzyme prodrug therapy (GDEPT); hydroxyethylnicotinamide; hypoxia; intestinal epithelium; lipophilicity; metronidazol; nalbuphine; neoplastic cells; nitroarenes; nitroimidazooxazine; nucleoside monophosphonate (NMP); omeprazole action; oseltamivir; oximes; permeability; pharmacokinetic properties; polymorphism; prodrug; protease inhibitors; solubility; structure ac-tivity relationship (SAR); sulindac; tenofovir disoproxil; transporter; transporter-mediated absorption; γ-aminobutyric acid (GABA)
Document Type: Research Article
Publication date: November 1, 2010
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