Medicinal chemistry strategies to minimize phospholipidosis.
Drug-induced phospholipidosis is characterised by an excessive accumulation of polar phospholipids in cells or tissues. However, from a toxicological perspective the functional consequences of phospholipidosis remain uncertain and a regulatory position unclear. As a consequence, to minimize compound development risk pharmaceutical companies are beginning to proactively address phospholipidosis within drug discovery programs, and implement strategies to identify compounds predicted to show no phospholipidosis. Examples of optimization of compounds to minimize phospholipidosis, and the status of current in silico prediction models, are presented and discussed.
Ratcliffe
Andrew J
AJ
Department of Medicinal Chemistry, Cellzome Ltd, Chesterford Research Park, Little Chesterford, Cambridge, UK. andrew.ratcliffe@cellzome.com
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000639:trends; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry; D010743:Phospholipids / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D010743:Phospholipids