Delving into the Latest Updates on Brezivaptan with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

AVPR1B

Mechanism

AVPR1B antagonists(Vasopressin V1b receptor antagonists)

Therapeutic Areas

Other Diseases

Active Indication-

Inactive Indication

Depressive Disorder, Major

Originator Organization

Taisho Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Taisho Pharmaceutical R&D, Inc.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Login to view timeline

Structure

Molecular FormulaC25H30ClN5O3

InChIKeyYCLGGNJZGIFVKX-UHFFFAOYSA-N

CAS Registry1370444-22-6

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.

14 Jul 2021·International Journal of NeuropsychopharmacologyQ2 · MEDICINE

Vasopressin V1B Receptor Antagonists as Potential Antidepressants

Q2 · MEDICINE

ReviewOA

Author: 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.

01 May 2021·Biopharmaceutics & Drug DispositionQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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 Deals associated with Brezivaptan

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 2	US	Taisho Pharmaceutical R&D, Inc.	03 Jul 2017

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03093025 (CTgov)	Phase 2	Depressive Disorder, Major	51	TS-121 10 mg (TS-121 10mg)	(bydhesflwh) = bwennyvfsf motfnqbdph (famketfouq, nxlpxbijtk - nerzbsnsqk) View more	-	09 Dec 2019
				TS-121 50 mg (TS-121 50mg)	(bydhesflwh) = wvuzkkscxp motfnqbdph (famketfouq, mzdzcazujo - ublljulqbf) View more