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Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design.

Abstract：

:Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore is equally important. Control of χ-space utilizes conformationally constrained amino acids that favor, disfavor, or exclude the gauche (-), the gauche (+), or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of χ1- and χ2-space. The manifold applications for cyclized analogues of the aromatic amino acids Phe, Tyr, Trp, and His within peptide medicinal chemistry are showcased herein with examples of enzyme inhibitors and ligands for G protein-coupled receptors.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Van der Poorten O,Knuhtsen A,Sejer Pedersen D,Ballet S,Tourwé D

doi

10.1021/acs.jmedchem.6b01029

subject

Has Abstract

pub_date

2016-12-22 00:00:00

pages

10865-10890

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

59

pub_type

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