Drug Induced Liver Injury (DILI). Mechanisms and Medicinal Chemistry Avoidance/Mitigation Strategies

Journal of Medicinal Chemistry
Bryan H Norman

Abstract

Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI risk. Literature assessments and retrospective analyses using verified DILI-associated drugs from the Liver Tox Knowledge Base (LTKB) have been used to derive the predictive value of each end point, along with combination approaches of multiple methods. In vitro assays to assess inhibition of the bile salt export pump (BSEP), mitotoxicity, reactive metabolite (RM) formation, and hepatocyte cytolethality, along with physicochemical properties and clinical dose provide useful DILI predictivity. This Perspective also highlights some of the strategies used by medicinal chemists to reduce DILI risk during the optimization of drug candidates.

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Citations

Feb 13, 2021·Clinical Toxicology : the Official Journal of the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists·Jiabing Wang
Feb 15, 2021·European Journal of Medicinal Chemistry·Zdeněk DvořákSridhar Mani
Apr 25, 2021·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Min TianJiang Zheng
Jul 26, 2021·Clinics and Research in Hepatology and Gastroenterology·Jorge Lucas de Sousa MoreiraJucier Gonçalves Júnior

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