Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme.

Razuprotafib, a sulphamic acid-containing phosphatase inhibitor, is shown to undergo enzymatic oxidation and methylation to form a major metabolite in monkey and human excreta with an value of 633.LC-MS/MS analysis of samples derived from incubations of razuprotafib with human liver microsomes and recombinant CYP2C8 enzyme has elucidated the metabolic pathway for formation of the thiol precursor to the S-methyl metabolite MS633 ( 633).Under conditions, the major pathway of razuprotafib metabolism involves extensive oxidation of the thiophene and phenyl rings.

The disposition of subcutaneous injected C-razuprotafib (C-AKB-9778), a sulphamic acid phosphatase inhibitor, in nonclinical species and human.

The disposition of radioactivity following subcutaneous C-razuprotafib, a Tie2 activator, was explored in multiple species.The absorption and clearance of razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.

A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure.

Purpose: Tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2) activation in Schlemm's canal (SC) endothelium is required for the maintenance of IOP, making the angiopoietin/Tie2 pathway a target for new and potentially disease modifying glaucoma therapies. The goal of the present study was to examine the effects of a Tie2 activator, AKB-9778, on IOP and outflow function.

Methods: AKB-9778 effects on IOP was evaluated in humans, rabbits, and mice.

The influence of physicochemical properties on the reactivity and stability of acyl glucuronides .

1. Formation of 1-O-acyl-β-d-glucuronide conjugates is a significant pathway in the metabolism of drugs containing a carboxylic acid group. The formation of acyl glucuronides results in an increase in both the aqueous solubility and molecular mass of the conjugate in comparison to the parent drug and thus facilitates excretion in both urine and bile.

Ca(2+) and frequency dependence of exocytosis in isolated somata of magnocellular supraoptic neurones of the rat hypothalamus.

In addition to action potential-evoked exocytotic release at neurohypophysial nerve terminals, the neurohormones arginine vasopressin (aVP) and oxytocin (OT) undergo Ca(2+)-dependent somatodendritic release within the supraoptic and paraventricular hypothalamic nuclei. However, the cellular and molecular mechanisms that underlie this release have not been elucidated. In the present study, the whole-cell patch-clamp technique was utilized in combination with high-time-resolved measurements of membrane capacitance (C(m)) and microfluorometric measurements of cytosolic free Ca(2+) concentration ([Ca(2+)](i)) to examine the Ca(2+) and stimulus dependence of exocytosis in the somata of magnocellular neurosecretory cells (MNCs) isolated from rat supraoptic nucleus (SON).