Delving into the Latest Updates on Sembragiline with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Sembragiline (USAN/INN)

+ [1]

Target

MAO-B

Mechanism

MAO-B inhibitors(Monoamine oxidase B inhibitors)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication-

Inactive Indication

Alzheimer DiseaseSmoking Cessation

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization-

Inactive Organization

Evotec International GmbHHoffmann-La Roche, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC19H19FN2O3

InChIKeyVMAVCCUQTALHOB-INIZCTEOSA-N

CAS Registry676479-06-4

A 2 PART STUDY IN HEALTHY SUBJECTS: PART A: A MULTIPLE DOSE, RANDOMIZED, PLACEBO CONTROLLED STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF SUPRA-THERAPEUTIC DOSES OF RO4602522; PART B: A MULTIPLE-DOSE, RANDOMIZED, DOUBLE-BLIND, DOUBLE DUMMY, PLACEBO CONTROLLED, POSITIVE-CONTROL, PARALLEL GROUP STUDY TO INVESTIGATE THE EFFECT OF RO4602522 ON THE QTC INTERVAL

This is a 2 part study to evaluate the safety and tolerability of supra-therapeutic doses of RO4602522 (Part A); and to investigate the effect of RO4602522 on the QTcF interval in healthy volunteers (Part B). Part A of the study will be a multiple-dose, randomized, double-blind, placebo-controlled study. Participants will be randomized to receive daily, oral doses of either RO4602522 or placebo for ten days. Part B of the study will be a multiple-dose, randomized, double-blind, double-dummy, placebo controlled, positive-control, parallel group study. Participants will be randomized to receive either multiple or single doses of RO4602522 or to receive single doses of moxifloxacin for 11 days. Pharmacokinetic parameters will be assessed for Parts A and B; and continuous ECG recordings will be made during Part B.

Start Date01 Apr 2014

Sponsor / Collaborator

Hoffmann-La Roche, Inc.

JPRN-JapicCTI-142605 / Unknown statusPhase 1

A multi center, open label study to assess the inhibiton of Brain MAO-B by RG1577 after repeated dosing in Japanese patients with Alzheimers Disease using positron emission tomography (PET)

Start Date01 Apr 2014

Sponsor / Collaborator

Chugai Pharmaceutical Co., Ltd.

100 Clinical Results associated with Sembragiline

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100 Translational Medicine associated with Sembragiline

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100 Patents (Medical) associated with Sembragiline

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6

Literatures (Medical) associated with Sembragiline

01 Jan 2018·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Synthesis and evaluation of biaryl derivatives for structural characterization of selective monoamine oxidase B inhibitors toward Parkinson’s disease therapy

Q3 · MEDICINE

Article

Author: Siwon Kim ; Hyeon Jeong Kim ; Yong Sup Lee ; Seul Ki Yeon ; Gyoonhee Han ; Ki Duk Park ; Ji Won Choi ; Jong Hyun Park ; Ae Nim Pae ; Yong Sun Bahn ; Bo Ko Jang ; Su Jeong Shin ; Ye Rim Lee

Benzyloxyphenyl moiety is a common structure of highly potent, selective and reversible inhibitors of monoamine oxidase B (MAO-B), safinamide and sembragiline. We synthesized 4-(benzyloxy)phenyl and biphenyl-4-yl derivatives including halogen substituents on the terminal aryl unit. In addition, we modified the carbon linker between amine group and the biaryl linked unit. Among synthesized compounds, 12c exhibited the most potent and selective MAO-B inhibitory effect (hMAO-B IC₅₀: 8.9 nM; >10,000-fold selectivity over MAO-A) as a competitive inhibitor. In addition, 12c showed greater MAO-B inhibitory activity and selectivity compared to well-known MAO-B inhibitors such as selegiline, safinamide and sembragiline. In the MPTP-induced mouse model of Parkinson's disease (PD), 12c significantly protected the tyrosine hydroxylase (TH)-immunopositive DAergic neurons and attenuated the PD-associated behavioral deficits. This study suggests characteristic structures as a MAO-B inhibitor that may provide a good insight for the development of therapeutic agents for PD.

01 Sep 2017·Journal of Pharmacology and Experimental TherapeuticsQ3 · MEDICINE

Sembragiline: A Novel, Selective Monoamine Oxidase Type B Inhibitor for the Treatment of Alzheimer’s Disease

Q3 · MEDICINE

Article

Author: Andersen, Julie K ; Messer, Juerg ; Siddiqui, Almas ; Rajagopalan, Subramanian ; Cesura, Andrea M ; Chinta, Shankar J ; Nave, Stephane ; Grueninger, Fiona ; Wyler, Rene ; Bohrmann, Bernd ; Rane, Anand ; Pähler, Axel ; Loetscher, Hansruedi ; Ellenbroek, Bart ; Prinssen, Eric ; Borroni, Edilio

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.

23 Jun 2017·Journal of Alzheimer's DiseaseQ3 · MEDICINE

Sembragiline in Moderate Alzheimer’s Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD)

Q3 · MEDICINE

Article

Author: Fontoura, Paulo ; Ricci, Benedicte ; Czech, Christian ; Nikolcheva, Tania ; Delmar, Paul ; Nave, Stephane ; Muelhardt, Nicoletta Milani ; Savola, Juha-Matti ; Dukart, Juergen ; Gilaberte, Inma ; Mannino, Marie ; Grimmer, Timo ; Doody, Rachelle S. ; Boada, Merce ; Pauly-Evers, Meike ; Lanctot, Krista ; Gerlach, Irene ; Carey, Tracie ; Borroni, Edilio ; Moran, Emma ; Santarelli, Luca ; Ostrowitzki, Susanne

BACKGROUNDSembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD).OBJECTIVETo evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.METHODSIn this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks.RESULTSNo differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p = 0.014; 1 mg) and - 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median).CONCLUSIONSThis study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

100 Deals associated with Sembragiline

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External Link

KEGG	Wiki	ATC	Drug Bank
D11224	-	-	-

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	CZ	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	DE	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	GB	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	PL	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	AU	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	US	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	SE	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	CA	Hoffmann-La Roche, Inc.	24 Oct 2012
Alzheimer Disease	Phase 2	KR	Hoffmann-La Roche, Inc.	24 Oct 2012
Smoking Cessation	Phase 2	DE	Evotec International GmbH	01 Feb 2008