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Allen B. Reitz - One of the best experts on this subject based on the ideXlab platform.

  • metabolism of the new Anxiolytic Agent a pyrido 1 2 benzimidazole pbi analog rwj 53050 in rat and human hepatic s9 fractions and in dog identification of cytochrome p450 isoforms mediated in the human microsomal metabolism
    European Journal of Drug Metabolism and Pharmacokinetics, 2006
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro and in vivo metabolism of RWJ-53050, an Anxiolytic Agent, was investigated after incubation with rat and human hepatic S9 fractions, and human microsomes and 7 microsomes containing individual human CYP isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in the presence of NADPH-generating system, and a single oral dose administration to dogs (30 mg/kg). Unchanged RWJ-53050 (≥74% of the sample in vitro; ⪯13% in vivo) plus 16 metabolites were profiled, quantified and tentatively identified based on the API-MS and MS/MS data. The formation of RWJ-53050 metabolites are via the 5 pathways: 1.N/O-demethylation, 2. phenylhydroxylation, 3. pyrido-oxidation, 4. dehydration, and 5. conjugation. Pathway 1 formedO-desmethyl-phenyl-RWJ-53050 (M1, <1–12% in vitro & in vivo), O-desmethyl-benzimidazole-RWJ-53050 (M2), and N-desmethyl-RWJ-53050 (M3) (M2 & M3, ⪯3% in vitro & in vivo). Pathway 2 generated hydroxy-benzimidazole-RWJ-53050 (M4), hydroxy-phenyl-RWJ-53050 (M5), and hydroxy-phenyl-M4 (M9) (⪯3% in vitro & in vivo). Pathway 3 formed 2 trace oxidized metabolites, hydroxy-pyrido-RWJ-53050 (M6, ⪯1% in vitro) and oxo-pyrido-RWJ-53050 (M8, <1% in vitro) and in conjunction with pathway 1 produced 2 trace dioxidized metabolites, OH-benzimidazole-M6 (M10) and OH-benzimidazole-M8 (M11) (in vitro). Pathway 4 formed a minor dehydrated metabolite of M6 (M7, 3%, in vitro). Pathway 5 produced 3 in vivo conjugates, Ml-glucuronide (M14,17%), M5-glucuronide (M15,50%), and M5-sulfate (M16,10%). RWJ-53050 is substantially metabolized in vitro in the rat and human, and extensively metabolized in vivo in the dog. formation of oxidized metabolites, Ml, M2, M4, M5 and M9.

  • Metabolism of the new Anxiolytic Agent, a pyrido[1,2-]benzimidazole (PBI) analog (RWJ-53050), in rat and human hepatic S9 fractions, and in dog; identification of cytochrome p450 isoforms mediated in the human microsomal metabolism.
    European journal of drug metabolism and pharmacokinetics, 2006
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro and in vivo metabolism of RWJ-53050, an Anxiolytic Agent, was investigated after incubation with rat and human hepatic S9 fractions, and human microsomes and 7 microsomes containing individual human CYP isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in the presence of NADPH-generating system, and a single oral dose administration to dogs (30 mg/kg). Unchanged RWJ-53050 (≥74% of the sample in vitro; ⪯13% in vivo) plus 16 metabolites were profiled, quantified and tentatively identified based on the API-MS and MS/MS data. The formation of RWJ-53050 metabolites are via the 5 pathways: 1.N/O-demethylation, 2. phenylhydroxylation, 3. pyrido-oxidation, 4. dehydration, and 5. conjugation. Pathway 1 formedO-desmethyl-phenyl-RWJ-53050 (M1,

  • Metabolism of the new nonbenzodiazepine Anxiolytic Agent, RWJ-51204, in mouse, rat, dog, monkey and human hepatic S9 fractions, and in rats, dogs and humans
    European journal of drug metabolism and pharmacokinetics, 2004
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro and in vivo metabolism of the nonbenzodiazepine Anxiolytic Agent, RWJ-51204 was investigated after incubation with mice, rat, dog, monkey, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral dose administration to rats (100 mg/kg), dogs (5 mg/kg), and humans (2.5 mg/subject). Plasma and red blood cells (2 h, rat) and urine samples (0–24 h, rat, dog and human) were obtained postdose. Unchanged RWJ-51204 (39–93% of the sample in vitro; ≤5% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data, and by comparison of synthetic samples.

  • Human hepatic metabolism of the Anxiolytic Agent, RWJ-51521--API-MS/MS identification of metabolites.
    European journal of drug metabolism and pharmacokinetics, 2004
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The In vitro metabolism of the Anxiolytic Agent, RWJ-51521 was conducted after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-51521 (30% of the sample) and a total of 11 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS/MS data. The 4 proposed metabolic pathways for RWJ-51521 are: (1) N/O-dealkylation, (2) phenylhydroxylation, (3) pyrido-oxidation, and (4) dehydration. Pathway 1 formed 2 major and 3 minor N/O-desalkyl metabolites (Ml & M3,50%) and in conjunction with pathway 4, formed 2 moderate dehydrated metabolites (M4 & M5, 14%). Pathways 2 and 3 alone, and in conjunction with pathway 4, produced 4 minor metabolites (each ≤2%). RWJ-51521 is extensively metabolized in human hepatic S9 fraction.

  • In vitro metabolism of the new Anxiolytic Agent, RWJ-52763 in human hepatic S9 fraction-API-MS/MS identification of metabolites.
    Journal of pharmaceutical and biomedical analysis, 2003
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro metabolism of the Anxiolytic Agent, RWJ-52763 was studied after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-52763 (64% of the sample) plus six metabolites (M1-M6) were profiled, quantified, and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-52763 are proposed, and the two metabolic pathways are: (1) N/O-dealkylation, and (2) phenylhydroxylation. Pathway 1 formed a major N-dealkylated metabolite, N-desethoxy-RWJ-52763 (M1, 22% of the sample) and 2 minor N/O-dealkylated metabolites, O-desmethyl-RWJ-52763 (M2; 2%) and N,N-didesethoxymethyl-RWJ-52763 (M3; 3%). Pathway 2 produced two hydroxyphenyl metabolites, hydroxydifluorophenyl-RWJ-52763 (M4; 4%) and hydroxyphenyl-pyrido-RWJ-52763 (M5; 3%) in small amounts, and in conjunction with step 1 formed a minor N-desethoxymethyl-M4 (M6; 1%). RWJ-52763 is substantially metabolized by this human hepatic S9.

L. A. Mckown - One of the best experts on this subject based on the ideXlab platform.

  • metabolism of the new Anxiolytic Agent a pyrido 1 2 benzimidazole pbi analog rwj 53050 in rat and human hepatic s9 fractions and in dog identification of cytochrome p450 isoforms mediated in the human microsomal metabolism
    European Journal of Drug Metabolism and Pharmacokinetics, 2006
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro and in vivo metabolism of RWJ-53050, an Anxiolytic Agent, was investigated after incubation with rat and human hepatic S9 fractions, and human microsomes and 7 microsomes containing individual human CYP isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in the presence of NADPH-generating system, and a single oral dose administration to dogs (30 mg/kg). Unchanged RWJ-53050 (≥74% of the sample in vitro; ⪯13% in vivo) plus 16 metabolites were profiled, quantified and tentatively identified based on the API-MS and MS/MS data. The formation of RWJ-53050 metabolites are via the 5 pathways: 1.N/O-demethylation, 2. phenylhydroxylation, 3. pyrido-oxidation, 4. dehydration, and 5. conjugation. Pathway 1 formedO-desmethyl-phenyl-RWJ-53050 (M1, <1–12% in vitro & in vivo), O-desmethyl-benzimidazole-RWJ-53050 (M2), and N-desmethyl-RWJ-53050 (M3) (M2 & M3, ⪯3% in vitro & in vivo). Pathway 2 generated hydroxy-benzimidazole-RWJ-53050 (M4), hydroxy-phenyl-RWJ-53050 (M5), and hydroxy-phenyl-M4 (M9) (⪯3% in vitro & in vivo). Pathway 3 formed 2 trace oxidized metabolites, hydroxy-pyrido-RWJ-53050 (M6, ⪯1% in vitro) and oxo-pyrido-RWJ-53050 (M8, <1% in vitro) and in conjunction with pathway 1 produced 2 trace dioxidized metabolites, OH-benzimidazole-M6 (M10) and OH-benzimidazole-M8 (M11) (in vitro). Pathway 4 formed a minor dehydrated metabolite of M6 (M7, 3%, in vitro). Pathway 5 produced 3 in vivo conjugates, Ml-glucuronide (M14,17%), M5-glucuronide (M15,50%), and M5-sulfate (M16,10%). RWJ-53050 is substantially metabolized in vitro in the rat and human, and extensively metabolized in vivo in the dog. formation of oxidized metabolites, Ml, M2, M4, M5 and M9.

  • Metabolism of the new Anxiolytic Agent, a pyrido[1,2-]benzimidazole (PBI) analog (RWJ-53050), in rat and human hepatic S9 fractions, and in dog; identification of cytochrome p450 isoforms mediated in the human microsomal metabolism.
    European journal of drug metabolism and pharmacokinetics, 2006
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro and in vivo metabolism of RWJ-53050, an Anxiolytic Agent, was investigated after incubation with rat and human hepatic S9 fractions, and human microsomes and 7 microsomes containing individual human CYP isoforms, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in the presence of NADPH-generating system, and a single oral dose administration to dogs (30 mg/kg). Unchanged RWJ-53050 (≥74% of the sample in vitro; ⪯13% in vivo) plus 16 metabolites were profiled, quantified and tentatively identified based on the API-MS and MS/MS data. The formation of RWJ-53050 metabolites are via the 5 pathways: 1.N/O-demethylation, 2. phenylhydroxylation, 3. pyrido-oxidation, 4. dehydration, and 5. conjugation. Pathway 1 formedO-desmethyl-phenyl-RWJ-53050 (M1,

  • Metabolism of the new nonbenzodiazepine Anxiolytic Agent, RWJ-51204, in mouse, rat, dog, monkey and human hepatic S9 fractions, and in rats, dogs and humans
    European journal of drug metabolism and pharmacokinetics, 2004
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro and in vivo metabolism of the nonbenzodiazepine Anxiolytic Agent, RWJ-51204 was investigated after incubation with mice, rat, dog, monkey, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral dose administration to rats (100 mg/kg), dogs (5 mg/kg), and humans (2.5 mg/subject). Plasma and red blood cells (2 h, rat) and urine samples (0–24 h, rat, dog and human) were obtained postdose. Unchanged RWJ-51204 (39–93% of the sample in vitro; ≤5% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data, and by comparison of synthetic samples.

  • Human hepatic metabolism of the Anxiolytic Agent, RWJ-51521--API-MS/MS identification of metabolites.
    European journal of drug metabolism and pharmacokinetics, 2004
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The In vitro metabolism of the Anxiolytic Agent, RWJ-51521 was conducted after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-51521 (30% of the sample) and a total of 11 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS/MS data. The 4 proposed metabolic pathways for RWJ-51521 are: (1) N/O-dealkylation, (2) phenylhydroxylation, (3) pyrido-oxidation, and (4) dehydration. Pathway 1 formed 2 major and 3 minor N/O-desalkyl metabolites (Ml & M3,50%) and in conjunction with pathway 4, formed 2 moderate dehydrated metabolites (M4 & M5, 14%). Pathways 2 and 3 alone, and in conjunction with pathway 4, produced 4 minor metabolites (each ≤2%). RWJ-51521 is extensively metabolized in human hepatic S9 fraction.

  • In vitro metabolism of the new Anxiolytic Agent, RWJ-52763 in human hepatic S9 fraction-API-MS/MS identification of metabolites.
    Journal of pharmaceutical and biomedical analysis, 2003
    Co-Authors: L. A. Mckown, Allen B. Reitz
    Abstract:

    The in vitro metabolism of the Anxiolytic Agent, RWJ-52763 was studied after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-52763 (64% of the sample) plus six metabolites (M1-M6) were profiled, quantified, and tentatively identified on the basis of API-MS/MS data. The metabolic pathways for RWJ-52763 are proposed, and the two metabolic pathways are: (1) N/O-dealkylation, and (2) phenylhydroxylation. Pathway 1 formed a major N-dealkylated metabolite, N-desethoxy-RWJ-52763 (M1, 22% of the sample) and 2 minor N/O-dealkylated metabolites, O-desmethyl-RWJ-52763 (M2; 2%) and N,N-didesethoxymethyl-RWJ-52763 (M3; 3%). Pathway 2 produced two hydroxyphenyl metabolites, hydroxydifluorophenyl-RWJ-52763 (M4; 4%) and hydroxyphenyl-pyrido-RWJ-52763 (M5; 3%) in small amounts, and in conjunction with step 1 formed a minor N-desethoxymethyl-M4 (M6; 1%). RWJ-52763 is substantially metabolized by this human hepatic S9.

Katsuo Toide - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacological characterization of the newly synthesized nociceptin/orphanin FQ-receptor agonist 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole as an Anxiolytic Agent.
    Journal of pharmacological sciences, 2008
    Co-Authors: Akiko Hirao, Aki Imai, Yutaka Sugie, Yoshinari Yamada, Shigeo Hayashi, Katsuo Toide
    Abstract:

    Abstract Nociceptin/orphanin FQ peptide (NOP)-receptor agonists have been shown to produce Anxiolytic-like effects in rodents subjected to various behavioral assays. Recently, we developed a new nonpeptide agonist of the NOP receptor, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB), as an Anxiolytic Agent. MCOPPB has a high affinity for the human NOP receptor (pKi = 10.07 ± 0.01) and selectivity for the NOP receptor over other members of the opioid receptor family: 12-, 270- and >1000-fold more selective for the NOP receptor than for the μ-, κ-, and δ-receptor, respectively. In an ex vivo binding study, MCOPPB (10 mg/kg, p.o.) inhibited signaling through the NOP receptor in the mouse brain, suggesting that it penetrated into the brain after it was orally administered. In the mouse Vogel conflict test, MCOPPB (10 mg/kg, p.o.) and diazepam (3 mg/kg, p.o.) elicited Anxiolytic-like effects, although MCOPPB produced a bell-shaped response curve. In addition, MCOPPB (10 mg/kg, p.o.) was still effective as an Anxiolytic Agent even after repeated administration for 5 days. MCOPPB at an oral dose of 10 mg/kg did not affect locomotor activity or memory, nor did it contribute to ethanol-induced hypnosis. On the other hand, the benzodiazepine-type Anxiolytic Agent diazepam caused memory deficits and enhanced ethanol-induced hypnosis. These findings suggest that MCOPPB –a compound with few adverse effects on the central nervous system –is a potential therapeutic Agent for the treatment of anxiety.

  • pharmacological characterization of the newly synthesized nociceptin orphanin fq receptor agonist 1 1 1 methylcyclooctyl 4 piperidinyl 2 3r 3 piperidinyl 1h benzimidazole as an Anxiolytic Agent
    Journal of Pharmacological Sciences, 2008
    Co-Authors: Akiko Hirao, Aki Imai, Yutaka Sugie, Yoshinari Yamada, Shigeo Hayashi, Katsuo Toide
    Abstract:

    Abstract Nociceptin/orphanin FQ peptide (NOP)-receptor agonists have been shown to produce Anxiolytic-like effects in rodents subjected to various behavioral assays. Recently, we developed a new nonpeptide agonist of the NOP receptor, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB), as an Anxiolytic Agent. MCOPPB has a high affinity for the human NOP receptor (pKi = 10.07 ± 0.01) and selectivity for the NOP receptor over other members of the opioid receptor family: 12-, 270- and >1000-fold more selective for the NOP receptor than for the μ-, κ-, and δ-receptor, respectively. In an ex vivo binding study, MCOPPB (10 mg/kg, p.o.) inhibited signaling through the NOP receptor in the mouse brain, suggesting that it penetrated into the brain after it was orally administered. In the mouse Vogel conflict test, MCOPPB (10 mg/kg, p.o.) and diazepam (3 mg/kg, p.o.) elicited Anxiolytic-like effects, although MCOPPB produced a bell-shaped response curve. In addition, MCOPPB (10 mg/kg, p.o.) was still effective as an Anxiolytic Agent even after repeated administration for 5 days. MCOPPB at an oral dose of 10 mg/kg did not affect locomotor activity or memory, nor did it contribute to ethanol-induced hypnosis. On the other hand, the benzodiazepine-type Anxiolytic Agent diazepam caused memory deficits and enhanced ethanol-induced hypnosis. These findings suggest that MCOPPB –a compound with few adverse effects on the central nervous system –is a potential therapeutic Agent for the treatment of anxiety.

Fen Yang - One of the best experts on this subject based on the ideXlab platform.

  • Prediction of a Therapeutic Dose for Buagafuran, a Potent Anxiolytic Agent by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Starting from Pharmacokinetics in Rats and Human.
    Frontiers in pharmacology, 2017
    Co-Authors: Fen Yang, Baolian Wang, Zhihao Liu, Xuejun Xia, Weijun Wang, Dali Yin, Li Sheng
    Abstract:

    Physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) models can contribute to animal-to-human extrapolation and therapeutic dose predictions. Buagafuran is a novel Anxiolytic Agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlusTM was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze. Buagafuran concentrations in human plasma were fitted and brain tissue concentrations were predicted by using a human PBPK model in which the predicted plasma profiles were in good agreement with observations. The results provided supportive data for the rational use of buagafuran in clinic.

  • prediction of a therapeutic dose for buagafuran a potent Anxiolytic Agent by physiologically based pharmacokinetic pharmacodynamic modeling starting from pharmacokinetics in rats and human
    Frontiers in Pharmacology, 2017
    Co-Authors: Fen Yang, Baolian Wang, Zhihao Liu, Xuejun Xia, Weijun Wang, Dali Yin, Li Sheng
    Abstract:

    Physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) models can contribute to animal-to-human extrapolation and therapeutic dose predictions. Buagafuran is a novel Anxiolytic Agent and phase I clinical trials of buagafuran have been completed. In this paper, a potentially effective dose for buagafuran of 30 mg t.i.d. in human was estimated based on the human brain concentration predicted by a PBPK/PD modeling. The software GastroPlusTM was used to build the PBPK/PD model for buagafuran in rat which related the brain tissue concentrations of buagafuran and the times of animals entering the open arms in the pharmacological model of elevated plus-maze. Buagafuran concentrations in human plasma were fitted and brain tissue concentrations were predicted by using a human PBPK model in which the predicted plasma profiles were in good agreement with observations. The results provided supportive data for the rational use of buagafuran in clinic.

  • simultaneous determination of a novel Anxiolytic Agent buagafuran and one metabolite in human plasma by ultra performance liquid chromatography tandem mass spectrometry
    Journal of Pharmaceutical and Biomedical Analysis, 2013
    Co-Authors: Fen Yang, Hongyun Wang, Qian Zhao, Xia Chen, Ji Jiang
    Abstract:

    Abstract A robust and validated ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method has been developed for the simultaneous determination of buagafuran and one metabolite (M1) in human plasma. The two analytes were extracted from plasma samples using tert-butyl methyl ether after addition of the internal standard and chromatographed on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) thermostatted at 35 °C with methanol–water (75:25, v/v) as the mobile phase at an isocratic flow rate of 0.4 mL/min. The detection was performed on an API 5500 mass spectrometer coupled with electrospray ionization (ESI) source in positive mode. The multiple reactions monitoring (MRM) transitions of m/z 245.2→109.1 and m/z 279.1→243.1 were used to quantify buagafuran and M1, respectively. The assay was validated over the concentration range of 0.5–200 ng/mL for the two analytes. Precision and accuracy are in accordance with the generally accepted criteria for bioanalytical methods. The extraction recovery and the matrix effect were investigated. This method was successfully applied to support a clinical study where multiple oral doses were administrated to healthy Chinese volunteers to investigate the pharmacokinetics, safety and tolerability of buagafuran.

Frank J. Villani - One of the best experts on this subject based on the ideXlab platform.

  • Process Research for the Synthesis of RWJ-51204, A Novel Anxiolytic Agent
    Organic Process Research & Development, 1999
    Co-Authors: Judith H. Cohen, Cynthia A. Maryanoff, Stephen Stefanick, And Kirk L. Sorgi, Frank J. Villani
    Abstract:

    RWJ-51204, the lead compound in our pyrido [1,2-a] benzimidazole (PBI) series, was shown to exhibit Anxiolytic efficacy in animal models at doses which did not cause central nervous system side effects commonly observed with other Anxiolytic Agents. To prepare supplies of drug substance for early toxicological and clinical studies, we needed to develop a safe and scaleable synthesis. Our main focus was to improve the last two steps of the process which involved formation of the penultimate carboxamide intermediate followed by alkylation using potentially toxic chloromethyl ethyl ether. Due to safety issues concerning storage and handling of this reAgent during the large scale synthesis, we investigated alternate routes to minimize potential exposure risks. The process research carried out for the final steps that led to the safe and cost-effective multi-kilogram synthesis of RWJ-51204 is described herein.