Brezivaptan(Brezivaptan) - 药物靶点：AVPR1B_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [2]

靶点

AVPR1B

作用机制

AVPR1B拮抗剂(血管加压素V1b受体拮抗剂)

治疗领域

其他疾病

在研适应症-

非在研适应症

重度抑郁症

原研机构

Taisho Pharmaceutical Co., Ltd.

在研机构-

非在研机构

Taisho Pharmaceutical R&D, Inc.

最高研发阶段终止临床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

分子式C25H30ClN5O3

InChIKeyYCLGGNJZGIFVKX-UHFFFAOYSA-N

CAS号1370444-22-6

关联

2

项与 Brezivaptan 相关的临床试验

NCT03093025 / Terminated临床2期

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Patients With Major Depressive Disorder With an Inadequate Response to Current Antidepressant Treatment

The purpose of this study is to evaluate the safety, tolerability, and efficacy of TS-121 as an adjunctive treatment for patients with major depressive disorder with an inadequate response to current antidepressant Treatment (SSRI, SNRI or bupropion).

开始日期2017-07-03

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

NCT02448212 / Completed临床1期

A Phase 1 Receptor Occupancy Study Using Positron Emission Tomography to Investigate Novel Ligand [11C]TASP0410699 Alone and Following Single Oral Dose Administrations of TS-121 in Healthy Adult (Male) Subjects

The purpose of this study is to evaluate the binding of a novel tracer, [11C]TASP0410699, using Positron Emission Tomography (PET) scans with or without dosing of TS-121

开始日期2015-05-01

申办/合作机构

Taisho Pharmaceutical R&D, Inc.

[+1]

100 项与 Brezivaptan 相关的临床结果

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100 项与 Brezivaptan 相关的转化医学

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100 项与 Brezivaptan 相关的专利（医药）

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4

项与 Brezivaptan 相关的文献（医药）

2022-04-01·Journal of Nuclear Medicine1区 · 医学

Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer ¹¹C-TASP699

1区 · 医学

Article

作者: Ozaki, Satoshi ; Huang, Yiyun ; Nishino, Izumi ; Ropchan, Jim ; Nabulsi, Nabeel B ; Lin, Shu-Fei ; Suhara, Tetsuya ; Sabia, Helene ; Henry, Shannan ; Labaree, David ; Gao, Hong ; Matuskey, David ; Carson, Richard E ; Naganawa, Mika ; Zhang, Ming-Rong ; Pracitto, Richard

Arginine vasopressin is a hormone that is synthesized mainly in the hypothalamus and stored in the posterior pituitary. Receptors for vasopressin are categorized into at least 3 subtypes (V_1A, V_1B, and V₂). Among these subtypes, the V_1B receptor (V_1BR), highly expressed in the pituitary, is a primary regulator of hypothalamic-pituitary-adrenal axis activity and thus a potential target for treatment of neuropsychiatric disorders such as depression and anxiety. N-tert-butyl-2-[2-(6-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP699) is a novel PET radiotracer with high affinity and selectivity for V_1BR. The purpose of this study was to characterize the pharmacokinetic and binding profiles of ¹¹C-TASP699 in humans and determine its utility in an occupancy study of a novel V_1BR antagonist, TS-121. Methods: Six healthy subjects were scanned twice with ¹¹C-TASP699 to determine the most appropriate kinetic model for analysis of imaging data and test-retest reproducibility of outcome measures. Nine healthy subjects were scanned before and after administration of TS-121 (active component: THY1773) to assess V_1BR occupancy. Metabolite-corrected arterial input functions were obtained. Pituitary time-activity curves were analyzed with 1- and 2-tissue-compartment (1TC and 2TC, respectively) models and multilinear analysis 1 (MA1) to calculate distribution volume (V _T). Relative test-retest variability (TRV) and absolute TRV were calculated. Since no brain region could be used as a reference region, percentage change in V _T after TS-121 administration was computed to assess its receptor occupancy and correlate with plasma concentrations of the drug. Results: ¹¹C-TASP699 showed high uptake in the pituitary and no uptake in any brain region. The 2TC model provided better fits than the 1TC model. Because the MA1 V _T estimates were similar to the 2TC V _T estimates, MA1 was the model of choice. The TRV of V _T was good (TRV, -2% ± 14%; absolute TRV, 11%). THY1773 reduced V _T in a dose-dependent fashion, with a half-maximal inhibitory concentration of 177 ± 52 ng/mL in plasma concentration. There were no adverse events resulting in discontinuation from the study. Conclusion: ¹¹C-TASP699 was shown to display appropriate kinetics in humans, with substantial specific binding and good reproducibility of V _T Therefore, this tracer is suitable for measurement of V_1BR in the human pituitary and the V_1BR occupancy of TS-121, a novel V_1BR antagonist.

2021-07-14·International Journal of Neuropsychopharmacology2区 · 医学

Vasopressin V1B Receptor Antagonists as Potential Antidepressants

2区 · 医学

ReviewOA

作者: Chaki, Shigeyuki

AbstractAccumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

2021-05-01·Biopharmaceutics & Drug Disposition4区 · 医学

Prediction of a clinically effective dose of THY1773, a novel V_1Breceptor antagonist, based on preclinical data

4区 · 医学

Article

作者: Mizuno‐Yasuhira, Akiko ; Endo, Hiromi ; Sabia, Helene D. ; Inatani, Shoko ; Kamiya, Makoto ; Nishino, Izumi

AbstractTHY1773 is a novel arginine vasopressin 1B (V1B) receptor antagonist that is under development as an oral drug for the treatment of major depressive disorder (MDD). Here we report our strategy to predict a clinically effective dose of THY1773 for MDD in the preclinical stage, and discuss the important insights gained by retrospective analysis of prediction accuracy. To predict human pharmacokinetic (PK) parameters, several extrapolation methods from animal or in vitro data to humans were investigated. The fu correction intercept method and two‐species‐based allometry were used to extrapolate clearance from rats and dogs to humans. The physiologically based pharmacokinetics (PBPK)/receptor occupancy (RO) model was developed by linking free plasma concentration with pituitary V1B RO by the Emax model. As a result, the predicted clinically effective dose of THY1773 associated with 50% V1B RO was low enough (10 mg/day, or at maximum 110 mg/day) to warrant entering phase 1 clinical trials. In the phase 1 single ascending dose study, TS‐121 capsule (active ingredient: THY1773) showed favorable PKs for THY1773 as expected, and in the separately conducted phase 1 RO study using positron emission tomography, the observed pituitary V1B RO was comparable to our prediction. Retrospective analysis of the prediction accuracy suggested that the prediction methods considering plasma protein binding, and avoiding having to apply unknown scaling factors obtained in animals to humans, would lead to better prediction. Selecting mechanism‐based methods with reasonable assumptions would be critical for the successful prediction of a clinically effective dose in the preclinical stage of drug development.

100 项与 Brezivaptan 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
重度抑郁症	临床2期	美国	Taisho Pharmaceutical R&D, Inc.	2017-07-03

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03093025 (CTgov)	临床2期	重度抑郁症	51	TS-121 10 mg (TS-121 10mg)	(壓簾選網餘艱選鹽糧窪) = 醖壓鏇鬱觸膚糧襯淵襯鏇觸繭蓋窪糧築遞鏇繭 (鏇鏇網鑰獵鏇範鹽網鑰, 網夢觸簾簾蓋獵築繭膚 ~ 艱遞積壓顧鹹鏇顧製糧) 更多	-	2019-12-09
				TS-121 50 mg (TS-121 50mg)	(壓簾選網餘艱選鹽糧窪) = 艱鑰餘範鑰繭網膚鏇鬱鏇觸繭蓋窪糧築遞鏇繭 (鏇鏇網鑰獵鏇範鹽網鑰, 窪廠襯廠衊膚鹹觸鹽鬱 ~ 網簾鹽鑰壓蓋衊壓顧膚) 更多