3 research outputs found
<i>N</i><sup>Δ</sup>âAcryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, StructureâActivity Relationships, and Pharmacokinetic Profiling
Transglutaminase
2 (TGase 2)-catalyzed transamidation represents
an important post-translational mechanism for protein modification
with implications in physiological and pathophysiological conditions,
including fibrotic and neoplastic processes. Consequently, this enzyme
is considered a promising target for the diagnosis of and therapy
for these diseases. In this study, we report on the synthesis and
kinetic characterization of <i>N</i><sup>Δ</sup>-acryloyllysine
piperazides as irreversible inhibitors of TGase 2. Systematic structural
modifications on 54 new compounds were performed with a major focus
on fluorine-bearing substituents due to the potential of such compounds
to serve as radiotracer candidates for positron emission tomography.
The determined inhibitory activities ranged from 100 to 10âŻ000
M<sup>â1</sup> s<sup>â1</sup>, which resulted in comprehensive
structureâactivity relationships. Structureâactivity
correlations using various substituent parameters accompanied by covalent
docking studies provide an advanced understanding of the molecular
recognition for this inhibitor class within the active site of TGase
2. Selectivity profiling of selected compounds for other transglutaminases
demonstrated an excellent selectivity toward transglutaminase 2. Furthermore,
an initial pharmacokinetic profiling of selected inhibitors was performed,
including the assessment of potential membrane permeability and liver
microsomal stability
<i>N</i><sup>Δ</sup>âAcryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, StructureâActivity Relationships, and Pharmacokinetic Profiling
Transglutaminase
2 (TGase 2)-catalyzed transamidation represents
an important post-translational mechanism for protein modification
with implications in physiological and pathophysiological conditions,
including fibrotic and neoplastic processes. Consequently, this enzyme
is considered a promising target for the diagnosis of and therapy
for these diseases. In this study, we report on the synthesis and
kinetic characterization of <i>N</i><sup>Δ</sup>-acryloyllysine
piperazides as irreversible inhibitors of TGase 2. Systematic structural
modifications on 54 new compounds were performed with a major focus
on fluorine-bearing substituents due to the potential of such compounds
to serve as radiotracer candidates for positron emission tomography.
The determined inhibitory activities ranged from 100 to 10âŻ000
M<sup>â1</sup> s<sup>â1</sup>, which resulted in comprehensive
structureâactivity relationships. Structureâactivity
correlations using various substituent parameters accompanied by covalent
docking studies provide an advanced understanding of the molecular
recognition for this inhibitor class within the active site of TGase
2. Selectivity profiling of selected compounds for other transglutaminases
demonstrated an excellent selectivity toward transglutaminase 2. Furthermore,
an initial pharmacokinetic profiling of selected inhibitors was performed,
including the assessment of potential membrane permeability and liver
microsomal stability
<i>N</i><sup>Δ</sup>âAcryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, StructureâActivity Relationships, and Pharmacokinetic Profiling
Transglutaminase
2 (TGase 2)-catalyzed transamidation represents
an important post-translational mechanism for protein modification
with implications in physiological and pathophysiological conditions,
including fibrotic and neoplastic processes. Consequently, this enzyme
is considered a promising target for the diagnosis of and therapy
for these diseases. In this study, we report on the synthesis and
kinetic characterization of <i>N</i><sup>Δ</sup>-acryloyllysine
piperazides as irreversible inhibitors of TGase 2. Systematic structural
modifications on 54 new compounds were performed with a major focus
on fluorine-bearing substituents due to the potential of such compounds
to serve as radiotracer candidates for positron emission tomography.
The determined inhibitory activities ranged from 100 to 10âŻ000
M<sup>â1</sup> s<sup>â1</sup>, which resulted in comprehensive
structureâactivity relationships. Structureâactivity
correlations using various substituent parameters accompanied by covalent
docking studies provide an advanced understanding of the molecular
recognition for this inhibitor class within the active site of TGase
2. Selectivity profiling of selected compounds for other transglutaminases
demonstrated an excellent selectivity toward transglutaminase 2. Furthermore,
an initial pharmacokinetic profiling of selected inhibitors was performed,
including the assessment of potential membrane permeability and liver
microsomal stability