Biotransformation of drug candidates often forms electrophilic intermediates that covalently modify biomolecules such as proteins and DNA. Such random tampering of the proteomic or genomic makeup of cells may have serious adverse results, such as undesirable immune responses with clinical phenotypes or mutagenicity/carcinogenicity endpoints. While it is difficult to preemptively link the modification of a biomolecule by a drug to a biochemical end-point and subsequently to a clinical adverse effect, it is generally accepted that bioactivation of drugs to reactive intermediates is an undesirable feature in a potential drug molecule. This presentation will discuss case studies where mechanistic approaches, employing organic chemistry tools, LC-MS fragmentation patterns and definitive structure elucidation by NMR, were used to dial out bioactivation liabilities from lead compounds in early discovery.

Mechanistic studies in metabolic activation in the context of drug discovery

244th National Meeting (2012)

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