A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Title: A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

Volume: 6 Issue: 3

Author(s): Amit S. Kalgutkar, Iain Gardner, R. Scott Obach, Christopher L. Shaffer, Ernesto Callegari, Kirk R. Henne, Abdul E. Mutlib, Deepak K. Dalvie, Jae S. Lee, Yasuhiro Nakai, John P. O'Donnell, Jason Boer and Shawn P. Harriman

Affiliation:

Keywords: bioactivation, reactive metabolite, inactivation, liver, idiosyncratic, toxicity, glutathione, drugs, amines

Abstract: The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to “black list” functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a “structural alert” in a new drug candidate undergoes bioactivation to reactive metabolites.

Cite this article as:

Kalgutkar S. Amit, Gardner Iain, Obach Scott R., Shaffer L. Christopher, Callegari Ernesto, Henne R. Kirk, Mutlib E. Abdul, Dalvie K. Deepak, Lee S. Jae, Nakai Yasuhiro, O'Donnell P. John, Boer Jason and Harriman P. Shawn, A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups, Current Drug Metabolism 2005; 6 (3) . https://dx.doi.org/10.2174/1389200054021799