10 research outputs found
Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats
Endothelial
dysfunction increases cardiovascular disease
risk in chronic kidney disease (CKD). This study
investigates whether VDR activation affects
endothelial function in CKD. The 5/6
nephrectomized (NX) rats with experimental
chronic renal insufficiency were treated with or
without paricalcitol, a VDR activator. Thoracic
aortic rings were precontracted with
phenylephrine and then treated with
acetylcholine or sodium nitroprusside. Uremia
significantly affected aortic relaxation
(−50.0 ± 7.4% in NX rats versus −96.2 ± 5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation was improved to –58.2 ± 6.0%, –77.5 ± 7.3%, and –90.5 ± 4.0% in NX rats treated with paricalcitol at 0.021, 0.042, and 0.083 μg/kg for two weeks, respectively, while paricalcitol at 0.042 μg/kg did not affect blood pressure and heart rate. Parathyroid hormone (PTH) suppression alone did not improve endothelial function since cinacalcet suppressed PTH without affecting endothelial-dependent vasorelaxation. N-omega-nitro-L-arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function. These results demonstrate that VDR activation improves endothelial function in CKD
Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists
Transient receptor
potential vanilloid 3 (TRPV3) is a Ca<sup>2+</sup>- and Na<sup>+</sup>-permeable channel with a unique expression pattern.
TRPV3 is found in both neuronal and non-neuronal tissues, including
dorsal root ganglia, spinal cord, and keratinocytes. Recent studies
suggest that TRPV3 may play a role in inflammation, pain sensation,
and skin disorders. TRPV3 studies have been challenging, in part due
to a lack of research tools such as selective antagonists. Herein,
we provide the first detailed report on the development of potent
and selective TRPV3 antagonists featuring a pyridinyl methanol moiety.
Systematic optimization of pharmacological, physicochemical, and ADME
properties of original lead <b>5a</b> resulted in identification
of a novel and selective TRPV3 antagonist <b>74a</b>, which
demonstrated a favorable preclinical profile in two different models
of neuropathic pain as well as in a reserpine model of central pain
Identification and Preliminary Characterization of a Potent, Safe, and Orally Efficacious Inhibitor of Acyl-CoA:Diacylglycerol Acyltransferase 1
A high-throughput screen against human DGAT-1 led to
the identification
of a core structure that was subsequently optimized to afford the
potent, selective, and orally bioavailable compound <b>14</b>. Oral administration at doses ≥0.03 mg/kg significantly reduced
postprandial triglycerides in mice following an oral lipid challenge.
Further assessment in both acute and chronic safety pharmacology and
toxicology studies demonstrated a clean profile up to high plasma
levels, thus culminating in the nomination of <b>14</b> as clinical
candidate ABT-046