Biotransformation and bioactivation reactions of alicyclic amines in drug molecules

Drug Metab Rev. 2014 Aug;46(3):379-419. doi: 10.3109/03602532.2014.924962. Epub 2014 Jun 9.


Aliphatic nitrogen heterocycles such as piperazine, piperidine, pyrrolidine, morpholine, aziridine, azetidine, and azepane are well known building blocks in drug design and important core structures in approved drug therapies. These core units have been targets for metabolic attack by P450s and other drug metabolizing enzymes such as aldehyde oxidase and monoamine oxidase (MAOs). The electron rich nitrogen and/or α-carbons are often major sites of metabolism of alicyclic amines. The most common biotransformations include N-oxidation, N-conjugation, oxidative N-dealkylation, ring oxidation, and ring opening. In some instances, the metabolic pathways generate electrophilic reactive intermediates and cause bioactivation. However, potential bioactivation related adverse events can be attenuated by structural modifications. Hence it is important to understand the biotransformation pathways to design stable drug candidates that are devoid of metabolic liabilities early in the discovery stage. The current review provides a comprehensive summary of biotransformation and bioactivation pathways of aliphatic nitrogen containing heterocycles and strategies to mitigate metabolic liabilities.

Keywords: Aliphatic cyclic amines; bioactivation; metabolism; mitigation; reactive intermediates.

Publication types

  • Review

MeSH terms

  • Amines / metabolism*
  • Animals
  • Biotransformation / physiology*
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Inactivation, Metabolic / physiology
  • Pharmaceutical Preparations / metabolism*


  • Amines
  • Pharmaceutical Preparations
  • Cytochrome P-450 Enzyme System