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

Pharmaceuticals

Polya G. Roydeva¹  Anna-Madeleine Beckmann¹  Marit Stirnberg¹  Jožko Cesar²  Danijel Kikelj²  Janez Ilaš²  Michael Gütschow¹ 

[1] Pharmaceutical Chemistry I, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53115 Bonn, Germany;Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia;

关键词: benzamidines;    4H-3;    1-benzothiazin-4-ones;    2;    3-dihydro-1;    4-benzodioxines;    3;    4-dihydro-2H-1;    4-benzoxazines;    matriptase-2;    protease inhibition;   

DOI  :  10.3390/ph9010002

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2016 by the authors; licensee MDPI, Basel, Switzerland.