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CHAPTER 8

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

This chapter summarizes some highlights of macrocyclic drug discovery in the area of GPCRs, integrins, and protein–protein interactions spanning roughly the last 30 years. Several examples demonstrate that incorporation of pharmacophores derived from natural peptide ligands into the context of a constrained macrocycle (“lock of the bioactive conformation”) has proven a powerful approach for the discovery of potent and selective macrocyclic drugs. In addition, it will be shown that macrocycles, due to their semi-rigid nature, can exhibit unique properties that can be beneficially exploited by medicinal chemists. Macrocycles can adapt their conformation during binding to a flexible protein target surface (“induced fit”), and due to their size, can interact with larger protein interfaces (“hot spots”). Also, macrocycles can display favorable ADME properties well beyond the rule of 5 in particular exhibiting favorable cell penetrating properties and oral bioavailability.

Publication details


Print publication date
16 Oct 2014
Copyright year
2015
Print ISBN
978-1-84973-701-2
PDF eISBN
978-1-78262-311-3
ePub eISBN
978-1-78262-316-8
From the book series:
Drug Discovery