Optimizing the Permeability and Oral Bioavailability of Macrocycles

Abstract

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.

Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies

“…This approach results in the formation of a pre-organized and semi-rigid entity that displays the amino acid side chains in a well-defined vector relationship for optimal binding and enhances the affinity of the inhibitor to the target enzyme by minimizing the entropy loss upon binding. Additional potential advantages of macrocyclic inhibitors include high stability to metabolizing enzymes, high selectivity and, frequently, increased cellular permeability [29] , [30] , [31] , [32] . We describe herein the structure-based design of macrocyclic inhibitors of norovirus 3CLpro where the side chain of the P 1 Gln primary substrate specificity residue is tethered to the P 3 residue via a triazole linker to yield macrocycles (I) ( Fig.…”

Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

“…An effective way of depeptitizing a linear peptide is through macrocyclization. [31][32][33][34] The preorganization and structural rigidity that characterize macrocyclic inhibitors frequently enhance pharmacological activity by reducing the entropic penalty associated with binding and, furthermore, increase proteolytic stability. 34 The effect of macrocyclization on cellular permeability and oral bioavailability is less predictable; however, these parameters are expected to be augmented when a macrocycle can engage in intramolecular hydrogen bonding.…”

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

“…Reduction of peptidyl character of the drugs typically enhances the cellular permeability, proteolytic stability, and oral bioavailability. 38,39 Thus, our goal in this present study is to rationally design novel inhibitors of HGFA, matriptase and hepsin which have much less peptide character. To that end, we introduced non-peptidyl functional groups into the P4 and P3 positions of the tetrapeptide inhibitors 1a and 1b, designed to make binding interaction in the corresponding S4 and S3 subsite pockets of the three proteases.…”