Characterization ofin vitrometabolites from human liver microsomes using directly coupled hplc-nmr: application to a phenoxathiin monoamine oxidase-A inhibitor

Q4 · MEDICINE

Article

Author: P. N. Sanderson ; J. C. Lindon ; B. C. Sweatman ; R. D. Farrant ; R. M. Wurm ; I. S. Silver ; J. P. Shockcor

1. The metabolism of 1-ethylphenoxathiin-10,10-dioxide (BW1370U87), an experimental compound designed as an inhibitor of monoamine oxidase-A for use as a possible anti-depression agent, has been studied in a human liver microsome preparation. 2. The identities of the metabolites have been determined using directly coupled hplc-1H nmr at 600 MHz in the stop-flow mode in this first study of in vitro xenobiotic metabolism using hplc-nmr. 3. The xenobiotic substances that were identified comprised the parent compound BW1370U87 (with -CH2CH3 at C1) together with sidechain-oxidized metabolites with C1 substituents of -CHOH.CH3, -CH2.CH2OH, -CHOH.CH2OH and -CH2.COOH, plus the unsubstituted phenoxathiin-10,10-dioxide.

01 Mar 1994·Rapid Communications in Mass SpectrometryQ3 · CHEMISTRY

The use of low‐energy collisionally activated dissociation negative‐ion tandem mass spectrometry for the characterization of dog and human urinary metabolites of the drug BW 1370U87

Q3 · CHEMISTRY

Article

Author: Robert L. Johnson ; Lisa St. John-Williams ; T. A. Baillie ; Lester C. E. Taylor ; Tom Johnson ; Sai Y. Chang

AbstractLiquid chromatography (LC) combined with atmospheric pressure chemical ionization mass spectrometry was used to identify phase I and II metabolites of the drug BW 1370U87 in dog and human urine. Additional analysis of individual high‐performance liquid chromatograph fractions collected from dog urine by combined gas chromatography/mass spectrometry identified one metabolite which was not detected by LC/MS methods. Using negative‐ion LC/MS, the majority of BW 1370U87 metabolites in human urine were identified as glucuronic acid conjugates of phase I oxidative metabolites. The negative‐ion fragmentation produced by low‐energy collisionally activated decomposition (CAD), studied by tandem mass spectrometry experiments, confirmed that these compounds were drug‐related and allowed metabolite structures to be assigned. Product‐ion spectra of the metabolites were dominated by the loss of neutral molecules from even‐electron deprotonated [M − H]− ions.

01 Jan 1993·Clinical neuropharmacologyQ4 · MEDICINE

Preclinical and early clinical studies with BW 1370U87, a reversible competitive monoamine oxidase-A inhibitor.

Q4 · MEDICINE

Review

Author: White, H L ; Ascher, J A

BW 1370U87 is unique among potent inhibitors of monoamine oxidase-A (MAO-A) in that it contains no nitrogen. Like other MAO-A inhibitors, BW 1370U87 elevates neurotransmitter amines in the brain over the same dose range at which it exhibits positive activities in animal models of depressive illness. However, BW 1370U87 differs from most other MAO inhibitors in that its mechanism of action follows simple competitive kinetics, so that an unusually high concentration of tyramine in peripheral tissues may displace the inhibitor from MAO-A sites in the intestine and liver. In addition, BW 1370U87 concentrations in brains of rats appear much higher than in plasma, whereas extensive metabolism of the parent compound in the liver produces weaker MAO-A inhibitors with the same type of competitive mechanism. Early phase-I safety trials at acute doses up to 2,000 mg of BW 1370U87 showed no adverse reactions, whereas MHPG in urine was decreased, indicating that in vivo inhibition of MAO-A was achieved in humans. Thus BW 1370U87 represents a new agent with potential therapeutic application in depression and other CNS illnesses.

100 Deals associated with BW-1370U87

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Phase 1	US	Krenitsky Pharmaceuticals, Inc.	-
Depressive Disorder	Phase 1	-	Krenitsky Pharmaceuticals, Inc.	-
Depressive Disorder, Major	Phase 1	US	GSK Plc	-

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