fingolimod hydrochloride salt fty720  (LC Laboratories)

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Mass Spectrometer Settings Used for Metabolite Profiling of FTY720-C2 and FTY720-Mitoxy.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Mass Spectrometry

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Pharmacokinetic Study Design for FTY720-C2 and FTY720-Mitoxy.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques:

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Intrinsic Clearance in Liver Microsomes.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques:

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Summary of the structural characterization by LC-MS/MS of FTY720-C2 Metabolites Identified in Rat and Human Hepatocytes.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques:

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Summary of the structural characterization by LC-MS/MS of FTY720-Mitoxy Metabolites Identified in Rat and Human Hepatocytes.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques:

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Using 1 μM of FTY720-C2, we incubated rat (a) and human (b) hepatocytes to obtain the metabolite profile. To simplify presentation, the 0 min incubation time point, data are intentionally not shown. Legend: C2 , FTY720-C2 C2-carboxylic acid; C4 , FTY720-C2 C4-carboxylic acid; C6 , FTY720-C2 C6-carboxylic acid; C8 , FTY720-C2 C8-carboxylic acid; FTY720-C2-OH , hydroxy FTY720-C2.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Incubation

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Mass spectrometry of FTY720-C2 and its metabolites, detected as protonated molecular ions [M+H] + are shown. Our rationale for identifying the structure of the metabolites is demonstrated using colored text and arrows, with blue product ions indicating losses of H 2 O and an N -acetyl group from [M+H] + , red product ions indicating hydroxylation, and green product ions associated with identified carboxylic acid modifications.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Mass Spectrometry

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Using 1 μM of FTY720-Mitoxy, we incubated rat (a) and human (b) hepatocytes to obtain metabolite profiles. To simplify presentation, the 0 min incubation time point data are intentionally not shown. Legend: C4 , FTY720-Mitoxy C4-carboxylic acid; C6 , FTY720-Mitoxy C6-carboxylic acid; C8 , FTY720-Mitoxy C8-carboxylic acid; FTY720-Mitoxy-OH , hydroxy FTY720-Mitoxy.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Incubation

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Mass spectrometry of FTY720-Mitoxy and metabolites detected [M + ] molecular ions. Blue text and arrows indicate losses of H 2 O from [M] + . The ion with a hydroxyl group is shown in red . Ions including a carboxylic acid are shown in green .

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Mass Spectrometry

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Relative Percent Distribution of FTY702-C2 and FTY720-Mitoxy.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Incubation

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: Mean plasma and brain concentrations of FTY720-C2 after IV dosing ( a ) and oral dosing ( b ) (black bar = plasma; white bar = brain); and of FTY720-Mitoxy after IV dosing ( c ) (▲ = plasma; ○ = brain). Units are in ng/mL for plasma and ng/g for brain. Data represent the mean ± SD of two experiments for each time point. Error bars were calculated for all samples and are present on the graphs. However, for samples with little variability error bars do not extend beyond the edges of the symbols so thus, are not apparent.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques:

Journal: PLoS ONE

Article Title: Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

doi: 10.1371/journal.pone.0162162

Figure Lengend Snippet: FTY720-C2 increased PP2A activity in adrenal glands at all time points following IV delivery ( a ) and oral delivery ( b ) as compared to untreated control mice. FTY720-Mitoxy increased PP2A activity in the adrenal gland at all time points after IV delivery ( c ). After oral delivery, FTY7220-Mitoxy was not absorbed and adrenal PP2A activity did not increase as compared to untreated controls ( d ). Two mice per time point were evaluated. Data represent mean ± SEM.

Article Snippet: Midazolam, diclofenac, glucose-6-phosphate dehydrogenase, glucose 6 phosphate, magnesium chloride, and testosterone (Sigma-Aldrich, St. Louis, MO); HPLC grade water, methanol, formic acid, and acetonitrile (Fisher Scientific, Pittsburgh, PA); cell free HepatoZYME-SFM (1x) medium (Gibco Life Technology, Grand Island, NY); C17 Sphingosine (Santa Cruz Biotechnology, Dallas, TX); Fingolimod hydrochloride salt (FTY720) (LC laboratories, Woburn, MA); the new compounds FTY720-C2 [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)acetamide] (MW 349.51 g/mol) and FTY720-Mitoxy [ N -(1-hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl)-3’-triphenylphosphoniumpropanamide] (MW 704.72 g/mol) were synthesized in Dr. Jeffery Arterburn’s laboratory (New Mexico State University, Las Cruces, NM) [ ].

Techniques: Activity Assay