ASP-8477(ASP-8477) - 药物靶点：FAAH_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

FAAH

作用方式

抑制剂

作用机制

FAAH抑制剂(脂肪酸酰胺水解酶抑制剂)

治疗领域

神经系统疾病内分泌与代谢疾病其他疾病

在研适应症-

非在研适应症

糖尿病周围神经性疼痛疱疹后神经痛

原研机构

Astellas Pharma, Inc.

在研机构-

非在研机构

Astellas Pharma Europe Ltd.

权益机构-

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C18H19N3O3

InChIKeyPLCMZPFTMOAGOE-UHFFFAOYSA-N

CAS号906737-25-5

关联

2

项与 ASP-8477 相关的临床试验

NCT02065349

/ Completed临床2期

A Phase 2a Enriched Enrollment Randomized Withdrawal Study to Assess Analgesic Efficacy and Safety of ASP8477 in Subjects With Peripheral Neuropathic Pain

The purpose of this study is to assess the painkilling efficacy of ASP8477 relative to mock (placebo) in patients that have been diagnosed with painful diabetic peripheral neuropathy or postherpetic neuralgia determined by the change in the average daily pain intensity in patients that initially respond favorably to treatment with ASP8477.

开始日期2014-02-24

申办/合作机构

Astellas Pharma Europe Ltd.

NCT02220777

/ Completed临床1期

A Double-blind, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Oral Doses of ASP8477 in Healthy Postmenopausal Females and Healthy Young Vasectomized Males, Including a Food Effect Part and a Part to Investigate the Interaction Between ASP8477 and Omeprazole

This is a 4-part study. Part I assesses the safety and tolerability of single ascending doses of ASP8477 or a placebo under fasted conditions in postmenopausal subjects. Part II is similar to part I except that the study is conducted in young, vasectomized males.
Part III assesses the effect of food (fed or fasted conditions) on ASP8477 in postmenopausal subjects.
Part IV assesses the drug-drug interaction between ASP8477 and omeprazole in postmenopausal subjects.

开始日期2010-11-01

申办/合作机构

Astellas Pharma Europe Ltd.

100 项与 ASP-8477 相关的临床结果

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100 项与 ASP-8477 相关的转化医学

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100 项与 ASP-8477 相关的专利（医药）

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5

项与 ASP-8477 相关的文献（医药）

2020-08-01·European Journal of Pharmacology3区 · 医学

ASP8477, a fatty acid amide hydrolase inhibitor, exerts analgesic effects in rat models of neuropathic and dysfunctional pain

3区 · 医学

Article

作者: Watabiki, Tomonari ; Sekizawa, Toshihiro ; Kiso, Tetsuo

Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E₂-, prostaglandin F_2α-, and bicuculline-induced allodynia in mice, showing broader analgesic spectra than existing drugs. In contrast, however, ASP8477 did not affect acute pain. These results indicate that the FAAH inhibitor ASP8477 exerts analgesic effects on neuropathic and dysfunctional pain, and its pharmacological properties are suitable for use in treating chronic pain.

2019-05-01·Clinical Pharmacology in Drug Development

A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels

Article

作者: Gangaram‐Panday, Shanti ; Collins, Christiane ; Treijtel, Nicoline ; Passier, Paul ; Fuhr, Rainard ; van Bruijnsvoort, Michel ; Ernault, Etienne

AbstractASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Because ASP8477 shows nonlinear pharmacokinetics, 3 doses (20, 60, and 100 mg) were evaluated. This study revealed changes in exposure (area under the concentration‐time curve) of the probe substrates after treatment with 20, 60, and 100 mg ASP8477, respectively, compared with substrates alone with geometric mean ratios of: midazolam, 119%, 151%, and 158%; losartan, 107%, 144%, and 190%; omeprazole, 213%, 456%, and 610%; and dextromethorphan, 138%, 340%, and 555% (with increasing doses, respectively). Overall, ASP8477 was a weak inhibitor for CYP3A4 and CYP2C9, a moderate to strong inhibitor for CYP2C19, and a weak to strong inhibitor for CYP2D6, with doses from 20 to 100 mg. This study confirmed that the Inje cocktail approach was able to detect relevant drug‐drug interactions impacting further development of ASP8477 and future therapeutic use. With the approach used here, the inhibiting effect of a perpetrator drug on different CYP enzymes can be evaluated, and at different doses, thereby supporting dose recommendations for potential interactions.

2018-06-01·Pain Medicine3区 · 医学

A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Phase I Study of Analgesic/Antihyperalgesic Properties of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Healthy Female Subjects

3区 · 医学

Article

作者: Yassen, Ashraf ; Passier, Paul ; Schaffler, Klaus ; Reeh, Peter

ObjectivesTo evaluate the analgesic/antihyperalgesic effect of ASP8477.DesignRandomized, double-blind, double-dummy, cross-over, placebo- and active comparator-controlled study.SettingHPR Dr. Schaffler GmbH, Munich, Germany.SubjectsHealthy female subjects aged 18-65 years.MethodsEligible subjects were randomly assigned to one of six treatment sequences and received multiple ascending doses of ASP8477, duloxetine, and placebo over three treatment periods (each consisting of 21-day dosing separated by 14-day washout periods). On the last day of each dose level, laser evoked potentials (LEPs) and visual analog scales (VAS pain) on capsaicin-treated skin at baseline and at multiple postdose time points were assessed. The primary end point was the difference in LEP N2-P2 peak-to-peak (PtP) amplitudes for ASP8477 100 mg vs placebo.ResultsTwenty-five subjects were randomized. In all subjects, LEP N2-P2 PtP amplitudes were numerically lower for ASP8477 100 mg vs placebo (P = 0.0721); in subjects who demonstrated positive capsaicin skin effects, a greater mean difference of -2.24 µV (P = 0.0146) was observed. Across all doses, LEP N2-P2 PtP amplitudes were lower for duloxetine compared with ASP8477 (mean difference -3.80 µV; P < 0.0001) or placebo (mean difference -5.21 µV; P < 0.0001). The effect of ASP8477 (all doses) on down-scoring the VAS pain score was significant compared with placebo (mean difference -2.55%; P < 0.0007).ConclusionsASP8477 was well tolerated in this study. Analysis of all subjects did not demonstrate a significant difference in LEP for ASP8477 100 mg over placebo but did in subjects who demonstrated positive capsaicin skin effects.

100 项与 ASP-8477 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
糖尿病周围神经性疼痛	临床2期	德国	Astellas Pharma Europe Ltd.	2014-02-24
糖尿病周围神经性疼痛	临床2期	英国	Astellas Pharma Europe Ltd.	2014-02-24
糖尿病周围神经性疼痛	临床2期	波兰	Astellas Pharma Europe Ltd.	2014-02-24
糖尿病周围神经性疼痛	临床2期	捷克	Astellas Pharma Europe Ltd.	2014-02-24
疱疹后神经痛	临床2期	英国	Astellas Pharma Europe Ltd.	2014-02-24
疱疹后神经痛	临床2期	波兰	Astellas Pharma Europe Ltd.	2014-02-24
疱疹后神经痛	临床2期	德国	Astellas Pharma Europe Ltd.	2014-02-24
疱疹后神经痛	临床2期	捷克	Astellas Pharma Europe Ltd.	2014-02-24