3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

Polya G Roydeva; Anna-Madeleine Beckmann; Marit Stirnberg; Jožko Cesar; Danijel Kikelj; Janez Ilaš; Michael Gütschow

doi:10.3390/ph9010002

3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

Pharmaceuticals (Basel). 2016 Jan 13;9(1):2. doi: 10.3390/ph9010002.

Authors

Polya G Roydeva¹, Anna-Madeleine Beckmann², Marit Stirnberg³, Jožko Cesar⁴, Danijel Kikelj⁵, Janez Ilaš⁶, Michael Gütschow⁷

Affiliations

¹ Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53115 Bonn, Germany. polq_roideva@abv.bg.
² Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53115 Bonn, Germany. annabeckmann@web.de.
³ Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53115 Bonn, Germany. marit.stirnberg@uni-bonn.de.
⁴ Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia. Jozko.Cesar@ffa.uni-lj.si.
⁵ Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia. Danijel.Kikelj@ffa.uni-lj.si.
⁶ Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia. Janez.Ilas@ffa.uni-lj.si.
⁷ Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53115 Bonn, Germany. guetschow@uni-bonn.de.

Abstract

The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with β-thalassemia. A sub-library of 64 compounds was screened for matriptase-2 inhibition and several active compounds were identified. (S)-Ethyl 2-(benzyl(3-((4-carbamidoylphenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-oxoacetate ((S)-12) showed an IC50 value of less than 10 µM. Structure-activity relationships were discussed and proposals to design new matriptase-2 inhibitors were made.

Keywords: 2,3-dihydro-1,4-benzodioxines; 3,4-dihydro-2H-1,4-benzoxazines; 4H-3,1-benzothiazin-4-ones; benzamidines; matriptase-2; protease inhibition.