In the field of drug discovery, retrometabolic drug design is a strategy for the design of safer drugs either using predictable metabolism to an inactive moiety or using targeted drug delivery approaches. The phrase retrometabolic drug design was coined by Nicholas Bodor.[1] The method is analogous to retrosynthetic analysis where the synthesis of a target molecule is planned backwards. In retrometabolic drug design, metabolic reaction information of drugs is used to design parent drugs whose metabolism and distribution can be controlled to target and eliminate the drug to increase efficacy and minimize undesirable side effects. The new drugs thus designed achieve selective organ and/or therapeutic site drug targeting and produce safe therapeutic agents and safe environmental chemicals. 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).[2][3][4][5][6]
Retrometabolic drug design loop that includes chemical delivery systems (CDS) design and soft drug (SD) design. Possible metabolic pathways for drugs (D) in general are indicated within the dashed box.
^Bodor N, Buchwald P (2012). Retrometabolic drug design and targeting. Hoboken, N.J.: John Wiley & Sons. p. 418. ISBN 978-0-470-94945-0.
^Bodor, N.; Buchwald, P. (1999). "Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems". Adv. Drug Deliv. Rev. 36 (2–3): 229–254. doi:10.1016/s0169-409x(98)00090-8. PMID 10837718.
^Miller, G. (2002). "Breaking down barriers". Science. 297 (5584): 1116–1118. doi:10.1126/science.297.5584.1116. PMID 12183610. S2CID 70373003.
^Regier, D.A.; Boyd, J.H.; Burke, J.D. Jr; Rae, D.S.; Myers, J.K.; Kramer, M.; Robins, L.N.; George, L.K.; Karno, M.; Locke, B.Z. (1988). "One-month prevalence of mental disorders in the United States". Arch. Gen. Psychiatry. 45 (11): 977–986. doi:10.1001/archpsyc.1988.01800350011002. PMID 3263101.
^Crone; Thompson, A.M. (1970). Crone, C.; Lassen, N.A. (eds.). Capillary Permeability: The Transfer of Molecules and Ions Between Capillary Blood and Tissue (C. ed.). Munksgaard: Copenhagen, Denmark. pp. 447–453.
^Oldendorf, W.H. (1974). "Lipid solubility and drug penetration of the blood–brain barrier". Proceedings of the Society for Experimental Biology and Medicine. 147 (3): 813–816. doi:10.3181/00379727-147-38444. PMID 4445171. S2CID 3156196.
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