|
Title
|
|
|
|
N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S : in silico design, synthesis and biochemical characterization
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (K-i = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4'-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (K-i = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Bioorganic and medicinal chemistry letters. - Oxford
| |
|
Publication
|
|
|
|
Oxford
:
2020
| |
|
ISSN
|
|
|
|
0960-894X
| |
|
DOI
|
|
|
|
10.1016/J.BMCL.2020.127420
| |
|
Volume/pages
|
|
|
|
30
:18
(2020)
, 6 p.
| |
|
Article Reference
|
|
|
|
127420
| |
|
ISI
|
|
|
|
000571824300001
| |
|
Pubmed ID
|
|
|
|
32763808
| |
|
Medium
|
|
|
|
E-only publicatie
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|