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Eur J Med Chem. 2016 Nov 10;123:746-762. doi: 10.1016/j.ejmech.2016.07.053. Epub 2016 Jul 25.

Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study.

Author information

1
Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
2
Laboratoire de Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles, Brussels, Belgium.
3
Department of Chemistry, Division of Biochemistry at the Vienna Institute of BioTechnology, BOKU-University of Natural Resources and Life Sciences, Muthgasse 18, A-1190, Vienna, Austria.
4
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
5
Laboratoire de Pharmacie Galénique et de Biopharmacie, Faculté de Pharmacie, Université Libre de Bruxelles (ULB), Brussels, Belgium.
6
Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
7
Laboratory of Experimental Medicine, A. Vésale Hospital, Faculty of Medicine, Université Libre de Bruxelles, Montigny-le-Tilleul, Belgium.
8
Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: pvantwer@ulb.ac.be.

Abstract

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).

KEYWORDS:

Bis-arylalkylamines derivatives; Docking; Myeloperoxidase selective inhibitors; Pharmacomodulation; Reversible inhibitors; SERT

PMID:
27537923
DOI:
10.1016/j.ejmech.2016.07.053
[Indexed for MEDLINE]

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