Strategies and Chemical Design Approaches to Reduce the Potential for Formation of Reactive Metabolic Species

Title: Strategies and Chemical Design Approaches to Reduce the Potential for Formation of Reactive Metabolic Species

Volume: 11 Issue: 4

Author(s): Upendra A. Argikar, James B. Mangold and Shawn P. Harriman

Affiliation:

Keywords: Bioactivation, reactive intermediates, structural alerts, isosteres, chemical design approach, covalent protein binding

Abstract: Metabolic activation of new chemical entities to reactive intermediates is routinely monitored in drug discovery and development. Reactive intermediates may bind to cellular macromolecules such as proteins, DNA and may eventually lead to cell death via necrosis, apoptosis or oxidative stress. The evidence that the ultimate outcome of metabolic activation is an adverse drug reaction manifested as in vivo toxicity, is at best circumstantial. However, understanding the process of bioactivation of structural alerts by trapping the reactive intermediates is critical to guide medicinal chemistry efforts in quest for safer and potent molecules. This commentary provides a brief introduction to adverse drug reactions and mechanisms of reactive intermediate formation for various functional groups, followed by a review of chemical design approaches, examples of such strategies, possible isosteric replacements for structural alerts and rationalization of laboratory approaches to determine reactive intermediates, as a guide to todays medicinal chemist.

Cite this article as:

A. Argikar Upendra, B. Mangold James and P. Harriman Shawn, Strategies and Chemical Design Approaches to Reduce the Potential for Formation of Reactive Metabolic Species, Current Topics in Medicinal Chemistry 2011; 11 (4) . https://dx.doi.org/10.2174/156802611794480891