2 research outputs found
Synthesis and Evaluation of Silanediols as Highly Selective Uncompetitive Inhibitors of Human Neutrophil Elastase
Chronic obstructive pulmonary disease (COPD) is an increasing
health
problem and is estimated to be the fifth leading cause of death in
2020 according to the World Health Organization. Current treatments
are only palliative, and therefore the development of new medicine
for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE)
is a serine protease that is heavily involved in the progression of
COPD through inflammatory breakdown of lung tissue. Consequently,
inhibitors of HNE are of great interest as therapeutics. In this article,
the development of silanediol peptide isosters as inhibitors of HNE
is presented. Kinetic studies revealed that incorporation of a silanediol
isoster in the inhibitor structure resulted in an uncompetitive mechanism
of inhibition, which further resulted in excellent selectivity. The
peculiar mechanism of inhibition and the resulting selectivity makes
the presented inhibitors promising leads for the development of new
HNE-inhibitor-based therapeutics for the treatment of COPD
Selective Arylsulfonamide Inhibitors of ADAM-17: Hit Optimization and Activity in Ovarian Cancer Cell Models
Activated
leukocyte cell adhesion molecule (ALCAM) is expressed
at the surface of epithelial ovarian cancer (EOC) cells and is released
in a soluble form (sALCAM) by ADAM-17-mediated shedding. This process
is relevant to EOC cell motility and invasiveness, which is reduced
by inhibitors of ADAM-17. In addition, ADAM-17 plays a key role in
EGFR signaling and thus may represent a useful target in anticancer
therapy. Herein we report our hit optimization effort to identify
potent and selective ADAM-17 inhibitors, starting with previously
identified inhibitor <b>1</b>. A new series of secondary sulfonamido-based
hydroxamates was designed and synthesized. The biological activity
of the newly synthesized compounds was tested in vitro on isolated
enzymes and human EOC cell lines. The optimization process led to
compound <b>21</b>, which showed an IC<sub>50</sub> of 1.9 nM
on ADAM-17 with greatly increased selectivity. This compound maintained
good inhibitory properties on sALCAM shedding in several in vitro
assays