N‐Aryl Isoleucine Derivatives as Angiotensin II AT₂ Receptor Ligands

Abstract

A novel series of ligands for the recombinant human AT2 receptor has been synthesized utilizing a fast and efficient palladium-catalyzed procedure for aminocarbonylation as the key reaction. Molybdenum hexacarbonyl [Mo(CO)6] was employed as the carbon monoxide source, and controlled microwave heating was applied. The prepared N-aryl isoleucine derivatives, encompassing a variety of amide groups attached to the aromatic system, exhibit binding affinities at best with Ki values in the low micromolar range versus the recombinant human AT2 receptor. Some of the new nonpeptidic isoleucine derivatives may serve as starting points for further structural optimization. The presented data emphasize the importance of using human receptors in drug discovery programs.

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

“…Behrends et al [67], also used compound 13 as a lead to evaluate fifteen new synthetic compounds. Thirteen of them showed higher activity than the lead compound 13 .…”

Palladium-Catalyzed Molybdenum Hexacarbonyl-Mediated Gas-Free Carbonylative Reactions

“…Scheme 14 Selected examples of biologically relevant target compounds synthesized by Mo(CO) 6 -mediated alkoxy-or aminocarbonylation. References: VACht, 86 kinase, 87 AT 2 R, 88 ghrelin, 89 (±)-ampelopsin B, 90 CDK8, 91 neurotensin, 92 α3β4 nAChR ligand 93 All of the examples described in the preceding pages have been conducted under a homogenous catalysis regime. Despite its immense popularity and utility, homogeneous catalysis suffers from two major drawbacks.…”

Evolution of Angiotensin Peptides and Peptidomimetics as Angiotensin II Receptor Type 2 (AT2) Receptor Agonists

“…The equipotency of Ang II and sarile (1), combined with the high affinity shown by Ang III towards AT2R, demonstrates that Asp 1 is not crucial for binding [33,34]. CGP42112A (2), a selective AT2R agonist extensively used to characterize this receptor [63][64][65], contains the same His-Pro-Ile C-terminal sequence as 1, while it bears a unique branched N-terminal structure as opposed to the rest of the linear peptides studied here (Figure 1) [66]. Compounds 3-6 (Figure 1) represent a series of conformationally restrained analogues where the central Tyr 4 -Ile 5 dipeptide fragment of Ang II is replaced by different γ-turn mimicking scaffolds.…”