Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design.
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.
Research Group of Organic Chemistry, Departments of Chemistry and Bio-Engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
Olivier
O
Van der Poorten
Department of Drug Design and Pharmacology, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
Astrid
A
Knuhtsen
Department of Drug Design and Pharmacology, University of Copenhagen , Jagtvej 162, 2100 Copenhagen, Denmark.
Daniel
D
Sejer Pedersen
Research Group of Organic Chemistry, Departments of Chemistry and Bio-Engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
Steven
S
Ballet
Research Group of Organic Chemistry, Departments of Chemistry and Bio-Engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
Dirk
D
Tourwé
D024322:Amino Acids, Aromatic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D024322:Amino Acids, Aromatic; D004791:Enzyme Inhibitors; D004798:Enzymes; D010455:Peptides; D057786:Peptidomimetics; D043562:Receptors, G-Protein-Coupled