Insects are known to have evolved different degradation mechanisms (such as oxidation via cytochrome P450s) to counter toxicity of the wide variety of natural and synthetic chemicals present in the environment. These mechanisms neutralize the active ingredient (AI), resulting in reduced bioavailability and duration of action. Therefore, optimization of AI properties in the early phases of insecticide discovery (phase 0 and phase 1) is highly critical to successfully bringing a product to market. Conventional metabolism studies are carried out by using radioactively labeled compounds. Since it is expensive and time-consuming to prepare radiolabeled materials, they are only used in later-phase metabolism trials (≥ Phase 1). At this later phase, the AI must already be well defined, so testing several analogs in parallel and selecting the best candidate is impractical. "Cold Metabolism" is an innovative approach for lead structure optimization to overcome the limitations of using radiolabeled compounds. The key component of this technique is high-resolution/accurate-mass mass spectrometry (HRAM-MS), which enables fast analysis to identify major metabolites of early-stage screening compounds in various studies. At BASF’s RTP site, we have been using LC–HRAM MS (Thermo Exactive and Q Exactive) to support early phases of insecticide discovery since 2011. Applications include the identification and semi-quantitation of metabolites for in vivo and in vitro samples of insecticide candidates, analysis of biomarkers to help establish modes of action, performance of degradation tests, and study of plant metabolism. We will present the instrumentation, methods, workflows and data associated with our cold metabolism work. Conducting such studies in the early discovery phases provides valuable data for better decision-making to move certain candidates to later development stages.

Cold metabolism: HRAM mass spectrometry support for the early phases of insecticide discovery

254th National Meeting (2017)

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