Protecting groups in drug structures

Are you aware of any therapeutic agent whose structure contains protecting group(s)? It is as if an intermediate en route to some target molecule was put through screening, revealing that it might be wise to leave the protecting group intact. Talk about the irony of chemical synthesis… I make this point in some of my classes and particularly like to mention the anti-epileptic drug topiramate as an example. There are also some really nice cases among recently approved peptide drugs. I think there is a molecule with a Cbz group at nitrogen, but I can’t recall its name at the moment.

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http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00176

Coming back to the “acetonide-rich” framework of topiramate, I want to mention an outstanding retrospective recently published by Dr. Bruce Maryanoff. He traces the discovery of topiramate to its origins and uses his narrative as an opportunity to remind us that the so-called phenotypic screens (rather popular these days) are nothing new. In fact, they represent the stomping grounds of drug discovery, a once widely accepted practice that eventually gave way to target-based approaches (rather unfortunately). My favorite passage in this paper is when Bruce recalls his fruitless attempts to convince upper management of Johnson&Johnson of the virtues of phenotypic screening. He says: “At the beginning of the 21st century, I felt like a lumbering dinosaur in the halls of the company…”.

12 thoughts on “Protecting groups in drug structures

  1. Thanks! This is a good example, although I suppose there is a difference between having a random protecting group hanging around (such as the acetonide) and using certain linkages that look like protecting groups, but are there for the pro-drug purposes…

  2. Aceylated/benzylated nucleosides are very commonly active in screens (protection of hydroxyls allows cellular penetration, cleaved by esterases once in the cell). You could consider sofosbuvir a protected monophosphate (or anything containing the ProTide moiety), tenofovir diisoproxil, etc. Esters/carbamates are pretty common in drugs to mask polar functional groups due to the ubiquity of esterases. Heck, even acetylsalicylic acid could be considered to have a “protecting group” as the active form is salicylic acid.

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