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

Abstract

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.

Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein–Ligand Complexes

“…Not unexpectedly, based on the stereospecificity of the ligand interaction revealed by the crystal structure of HTL0028125 (2), inversion of the stereochemistry of the spiro centre (11) or of the indazolylmethyl bearing carbon (12) led to major reductions in potency. Interestingly, the 7-methyl-1H-indazol-5-yl group of HTL0028016 (1) can be replaced with a benzofuran-3-yl group (13). Although the indazole NH had been shown to be involved in a hydrogen-bonded interaction with Asp71 RAMP1, the lipophilic character of the cavity and the flexibility of both Asp71 RAMP1 and Arg38 CLR consistent with the binding mode of telcagepant had shown that a nonhydrogen bonding lipophilic aryl group could bind effectively to that region of the CGRP receptor.…”

“…Absolute stereochemistries of compounds are as depicted in Tables 1−3. The benzofuranyl analogue (13) was prepared from racemic amino ester (21d) and the diastereoisomers separated by chromatography at the final stage.…”

Cyclic Peptide Design Guided by Residual Dipolar Couplings, J-Couplings, and Intramolecular Hydrogen Bond Analysis

“…Interest in macrocyclic peptides and their novel architectures has increased significantly as their potential for interacting with a variety of targets including GPCRs, , proteases, kinases, ATPases, and others has been recognized. − However, achieving good cellular permeability and bioavailability for cyclic peptides is anything but straightforward due to larger molecular weights and increased polar surface areas. One prominent exception is the naturally occurring cyclic undecapeptide, cyclosporin A, an orally active immunosuppressive drug that forms a ternary complex with cyclophilin and calcineurin and thereby inhibits T-cell activation .…”

Synthesis and Solution Self-Assembly Properties of Cyclic Rod–Coil Diblock Copolymers

“…With the findings of bioactive macrocycles, including cyclic peptides and circular RNAs, − cyclic block copolymers have attracted great research interests for their biomimic architectures and self-assembly properties. − These reported cyclic block copolymers are coil–coil copolymers since the flexible chains of linear precursors facilitate their intrachain reaction to cyclics following the traditional ring-closure method in dilute conditions. − However, most bioactive macrocycles are semirigid macromolecules. , Since it is well-known that rod–coil copolymers show more abundant self-assembly behaviors than their coil–coil counterparts, − cyclic rod–coil copolymers are envisaged to have distinct properties with the introduction of chain constraint. The challenge lies in the synthesis of their end-functionalized linear rod–coil precursors, in addition to the entropy penalty for the rod blocks to achieve suitable conformations during ring-closure reaction, which may hamper the formation of cyclic rod–coil diblock copolymers.…”

“…13−19 However, most bioactive macrocycles are semirigid macromolecules. 20,21 Since it is well-known that rod−coil copolymers show more abundant self-assembly behaviors than their coil−coil counterparts, 22−28 cyclic rod−coil copolymers are envisaged to have distinct properties with the introduction of chain constraint. The challenge lies in the synthesis of their end-functionalized linear rod−coil precursors, in addition to the entropy penalty for the rod blocks to achieve suitable conformations during ring-closure reaction, which may hamper the formation of cyclic rod−coil diblock copolymers.…”