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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Norman BH

doi

10.1021/acs.jmedchem.0c00524

subject

Has Abstract

pub_date

2020-10-22 00:00:00

pages

11397-11419

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章,评审

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