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CHAPTER 10

Optimizing the Permeability and Oral Bioavailability of Macrocycles

Macrocycles have a number of inherent advantages that improve their prospects for achieving oral bioavailability, even when their physical properties lie outside the traditional Rule-of-5 chemistry space. This chapter provides an overview of these advantages, with particular attention given to the potential for macrocycles to adopt three-dimensional conformations that overcome barriers to permeability. An overview of the relationship between physical properties and oral bioavailability is given along with a more detail description of permeability, including recent developments in using fundamental physics to predict passive permeability. A variety of orally bioavailable macrocycles is described, including both natural products and compounds discovered through medicinal chemistry. In addition, some structure property relationships are described, which were identified during the process of optimizing these macrocycles.

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
Citation:
From the book series:
Drug Discovery