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Utilizing mechanistic organic chemistry training to study drug metabolism in preclinical drug discovery/development

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Abstract

A fundamental knowledge of applied organic chemistry is an important weapon in the arsenal of drug metabolism scientists, particularly ones engaged in the design and/or the conduct of biotransformation studies or as drug hunters. Application of basic organic chemistry concepts (e.g., nucleophilicity/electrophilicity, bond polarity, electron flow, etc.) are important in elucidating structures of complex metabolites, arising from the metabolism of xenobiotics, and rationalizing the biotransformation mechanisms leading to their formation. An appreciation for the art of using mechanistic chemistry insights to study metabolic processes is usually gained during graduate training (MS and/or PhD) in academic laboratories specialized in the fields of chemical toxicology, medicinal chemistry, and/or enzymology. Select examples of academic research efforts, wherein mechanistic organic chemistry concepts were successfully applied to rationalize and establish structure-metabolism toxicology relationship trends for the oxidative metabolism of alicyclic amines are highlighted in this manuscript. The co-authors of this manuscript participated in some of this research work during their academic training, and went on toward a career in the pharmaceutical industry, where they applied their academic training toward studies on the metabolism of new drug substances, which also included efforts exploring the chemical basis for a toxicological consequence(s) in the preclinical discovery setting. The latter attribute is highlighted with a case study exploring metabolic activation pathways with a small molecule 5-HT2C agonist, which was genotoxic in the in vitro Ames assay.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics, Crinetics Pharmaceuticals, San Diego, CA, 92121, USA

    Deepak Dalvie

  2. Medicine Design, Pfizer Worldwide Research, Development, and Medical, 1 Portland St, Cambridge, MA, 02139, USA

    Amit S. Kalgutkar

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  1. Deepak Dalvie
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Correspondence to Deepak Dalvie or Amit S. Kalgutkar.

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Dr DD and Dr AK are employees of Crinetics Pharmaceuticals and Pfizer, respectively.

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Dalvie, D., Kalgutkar, A.S. Utilizing mechanistic organic chemistry training to study drug metabolism in preclinical drug discovery/development. Med Chem Res 32, 1922–1932 (2023). https://doi.org/10.1007/s00044-023-03085-z

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