Metabolism of common motifs used in drug design

During the course of 2022 we’ve created a few resources that look at drug metabolism of some of the motifs incorporated in drug structures by medicinal chemists. Here we assemble these three blogs for handy reference for our LinkedIn followers.

Metabolism of cyclopropyl groups: a double-edged sword

Cyclopropyl groups are an appealing substituent used in drug design because they impart constraint in aliphatic systems while retaining a high fraction of sp3. They can be used advantageously to diminish oxidative metabolism in some circumstances, but when coupled to amines can lead to potentially reactive intermediates. In this blog we take a quick look at the metabolism of a few drug structures containing cyclopropyl groups.

Metabolism of t-butyl groups in drugs: t for trouble?

The tert-butyl group is a common group present in many drugs across different therapeutic classes. Despite its simple bulky structure, t-butyl groups have unique properties and can serve to change or increase specificity, or act as steric shields to increase stability of compounds containing chemically or enzymatically susceptible groups. However, they are often subject to metabolism by a number of cytochrome P450 enzymes (CYPs). In this blog, we discuss metabolism of some drugs in which CYPs catalyse oxidation of tert-butyl groups and strategies used to circumvent this.

Bioisosteres that influence metabolism

The majority of reviews on the application of bioisosteres are focused on effects on potency. Here we focus on how bioisosteres can alter metabolism of a drug, exploring three common functional groups that have well known issues around metabolism, as well as innovative methods devised to address these issues.

Do let us know what else you'd like us to look at. We already have some thoughts for 2023 and it would be great to incorporate any ideas from our readers.