Aliphatic/aromatic amine-containing drugs cover a broad range of marketed therapeutics and possess a wide spectrum of physiochemical properties.  Retrospective analyses of their disposition characteristics in animals and human suggest that inclusion of basic amine centers in small molecule investigational drugs can confer several pharmacokinetic benefits including enhanced oral absorption (due to increased aqueous solubility of corresponding salt forms) and long elimination half-lives (due to increased steady state distribution volumes).  On the other hand, certain amine-containing drugs have gained dubious notoriety with respect to their off-target pharmacology (e.g., hERG channel blockade leading to cardiac arrhythemia) and preclinical toxicology, which in turn, is governed by their lipophilicity and basicity.  Furthermore, there are several reports associating amine-containing drugs (and drug candidates) with metabolism-driven genotoxicity, drug-drug interactions, and even idiosyncratic adverse drug reactions.  The lecture will summarize the current state-of-the-art on the facts and myths associating this otherwise attractive functionality with undesirable toxicological consequences, which has also led to its characterization as a "structural alert" in some cases.

Toxicity arising from amine-containing drugs: Where do we draw the line?

2019 Spring National Meeting

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