2 research outputs found
Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis
Recently,
we reported a novel role for KMO in the pathogenesis
of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase
(KMO) have previously been described as potential treatments for neurodegenerative
conditions and particularly for Huntington’s disease. However,
the inhibitors reported to date have insufficient aqueous solubility
relative to their cellular potency to be compatible with the intravenous
(iv) dosing route required in AP. We have identified and optimized
a novel series of high affinity KMO inhibitors with favorable physicochemical
properties. The leading example is exquisitely selective, has low
clearance in two species, prevents lung and kidney damage in a rat
model of acute pancreatitis, and is progressing into preclinical development
Mass Spectrometry Imaging for Dissecting Steroid Intracrinology within Target Tissues
Steroid concentrations within tissues
are modulated by intracellular
enzymes. Such “steroid intracrinology” influences hormone-dependent
cancers and obesity and provides targets for pharmacological inhibition.
However, no high resolution methods exist to quantify steroids within
target tissues. We developed mass spectrometry imaging (MSI), combining
matrix assisted laser desorption ionization with on-tissue derivatization
with Girard T and Fourier transform ion cyclotron resonance mass spectrometry,
to quantify substrate and product (11-dehydrocorticosterone and corticosterone)
of the glucocorticoid-amplifying enzyme 11β-HSD1. Regional steroid
distribution was imaged at 150–200 μm resolution in rat
adrenal gland and mouse brain sections and confirmed with collision
induced dissociation/liquid extraction surface analysis. In brains
of mice with 11β-HSD1 deficiency or inhibition, MSI quantified
changes in subregional corticosterone/11-dehydrocorticosterone ratio,
distribution of inhibitor, and accumulation of the alternative 11β-HSD1
substrate, 7-ketocholesterol. MSI data correlated well with LC-MS/MS
in whole brain homogenates. MSI with derivatization is a powerful
new tool to investigate steroid biology within tissues