Sir James Black’s advice that “the most fruitful basis for the discovery of a new drug is to start with an old drug” still holds true to a surprising degree. Retrometabolic drug design approaches provide general drug design strategies very much along the lines of the latter, as they usually start from a known lead structure and focus on designing safer, less toxic, and intrinsically better targeted drugs either through soft drug or chemical delivery system designs.
Retrometabolic drug design approaches represent systematic methodologies that thoroughly integrate structure–activity and structure–metabolism relationships and are aimed at designing safe, locally active compounds with an improved therapeutic index. They include two distinct methods. One approach is the design of soft drugs (SDs), new, active therapeutic agents, often isosteric or isoelectronic analogs of a lead compound, with a chemical structure specifically designed to allow predictable metabolism into inactive metabolites after exerting their desired therapeutic effect(s). The other approach is the design of chemical delivery systems (CDSs). CDSs are biologically inert molecules intended to enhance drug delivery to a particular organ or site and requiring several conversion steps before releasing the active drug.
Although both approaches involve chemical modifications of the molecular structure and both require enzymatic reactions to fulfill drug targeting, the principles of SD and CDS design are distinctly different. While CDSs are inactive as administered and sequential enzymatic reactions provide the differential distribution and ultimately release the active drug, SDs are active as administered and are designed to be easily metabolized into inactive species.
Assuming an ideal situation, with a CDS the drug is present at the site and nowhere else in the body because enzymatic processes produce the drug only at the site, whereas with an SD the drug is present at the site and nowhere else in the body because enzymatic processes destroy the drug at those sites. (reference [link to book])
N. Bodor, Z. Zubovics, I. Kurucz, S. Sólyom and E. Bodor, “Potent Analogs of Etiprednol Dicloacetate, a Second Generation of Soft Corticosteroids,” J. Pharm. Pharmacol., 69(12), 1745-1753, (2017). Read More
A. Samir, N. Bodor and T. Imai, “Identification of Esterases Involved in the Metabolism of Two Corticosteroid Soft Drugs,” Biochem. Pharmacol., 127, 82-89 (2017). Read More
E. T. Bodor, W.-M. Wu, R. Chandran and N. Bodor, “Enhanced Activity of Topical Hydrocortisone by Competitive Binding of Corticosteroid-Binding Globulin,” J. Pharm. Sci., 105, 2873-2878 (2016). Read More
P. Buchwald and N. Bodor, “Brain-Targeting Chemical Delivery Systems and Their Cyclodextrin-Based Formulations in Light of the Contributions of Marcus E. Brewster,” J. Pharm. Sci., accepted for publication (2016). Read More
P. Buchwald and N. Bodor, “Recent advances in the design and development of soft drugs,” Proceedings of the 9th Retrometabolism Based Drug Design and Targeting Conference, May 12-15, 2013, Orlando, FL, Pharmazie, 69(6), 403-413 (2014). Read More
W.-M. Wu, E. T. Bodor, J. Howes and N Bodor, “The effects of ∆1-cortienic acid on skin blanching, pharmacokinetics and stability of loteprednol etabonate,” Proceedings of the 8th Retrometabolism Based Drug Design and Targeting Conference, June 2-4, 2011, Graz, Austria, Pharmazie, 67(5), 406-410 (2012). Read More
N. Bodor and P. Buchwald, “Retrometabolic Drug Design and Targeting,” book, John Wiley & Sons, ISBN 978-0-470-94945-0, 405 pp. (2012). Read More
W.-M. Wu, Y. Tang, P. Buchwald and N. Bodor, “Pharmacokinetics and ∆1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats,” Proceedings of the 7th Retrometabolism Based Drug Design and Targeting Conference, May 10-13, 2009, Orlando FL, Pharmazie, 65(6), 412-416 (2010). Read More
E. Pinto, B. Zhang, S. Song, N. Bodor, P. Buchwald and G. Hochhaus, “Feasibility of localized immunosuppression: 2. PLA microspheres for the sustained local delivery of a soft immunosuppresent,” Proceedings of the 7th Retrometabolism Based Drug Design and Targeting Conference, May 10-13, 2009, Orlando FL, Pharmazie, 65(6), 429-435 (2010). Read More
P. Buchwald, N. Bocca, S. Marzorati, G. Hochhaus, N. Bodor, C. Stabler, N. S. Kenyon, L. Inberardi, R. D. Molano, C. Ricordi and A. Pileggi, “Feasibility of localized immunosuppression: 1. Exploratory studies with glucocorticoids in a biohybrid device designed for cell transplantation,” Proceedings of the 7th Retrometabolism Based Drug Design and Targeting Conference, May 10-13, 2009, Orlando FL, Pharmazie, 65(6), 421-428 (2010). Read More
N. Bodor and P. Buchwald, “Recent advances in retrometabolic drug design (RMDD) and development,” Proceedings of the 7th Retrometabolism Based Drug Design and Targeting Conference, May 10-13, 2009, Orlando FL, Pharmazie, 65(6), 395-403 (2010). Read More
N. Bodor and P. Buchwald, “Retrometabolism-Based Drug Design and Targeting,” In Burger’s Medicinal Chemistry, Drug Discovery and Development, Vol. 2: Discovering Lead Molecules, 7th ed. (D.J. Abraham, Ed.) Wiley: New York, (2010), chapter 3. Read More