Delving into the Latest Updates on Lanabecestat with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Lanabecestat (USAN), Lanabecestat Camsylate

+ [3]

Target

BACE1

Mechanism

BACE1 inhibitors(Beta-secretase 1 inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication

Alzheimer Disease

Inactive Indication

Liver DiseasesThrombosis

Originator Organization

AstraZeneca PLC

Active Organization

Eli Lilly & Co.

Lilly Asia Shanghai Representative OfficeAstraZeneca AB

Inactive Organization

AstraZeneca PLC

Drug Highest PhasePhase 3

First Approval Date-

RegulationSpecial Review Project (CN)

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Structure

Molecular FormulaC26H28N4O

InChIKeyWKDNQONLGXOZRG-HRNNMHKYSA-N

CAS Registry1383982-64-6

The study will evaluate the effect of oral contraceptive (birth control pill) on the blood level of lanabecestat when both are given together. Side effects will be monitored and documented. This study will last up to 27 days for each participant, not including screening. Screening is required within 42 days prior to first dose.

Start Date01 Jun 2018

Sponsor / Collaborator

Eli Lilly & Co.

[+1]

NCT03545087 / WithdrawnPhase 1

Pharmacokinetics of Lanabecestat (LY3314814) in Subjects With Impaired Renal Function

The purpose of the study is to determine whether lanabecestat can be safely prescribed in participants with kidney impairment without a dose adjustment.
Participants will be on study for up to 6 weeks; this includes a 2-week screening and a follow-up about 10 days after final drug administration.

Start Date01 Jun 2018

Sponsor / Collaborator

Eli Lilly & Co.

[+1]

NCT03499041 / WithdrawnPhase 1

Pharmacokinetics of LY3314814 in Subjects With Hepatic Impairment

The purpose of the study is to determine whether LY3314814 can be safely prescribed in participants with liver impairment without a dose adjustment. Participants will be on study for 11 days with follow-up about 7 days afterward.

Start Date01 Jun 2018

Sponsor / Collaborator

Eli Lilly & Co.

[+1]

100 Clinical Results associated with Lanabecestat

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100 Translational Medicine associated with Lanabecestat

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100 Patents (Medical) associated with Lanabecestat

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27

Literatures (Medical) associated with Lanabecestat

01 Apr 2024·Cytotherapy

Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity

Article

Author: Metierre, Cynthia ; Nagarajah, Rajini ; Bailey, Charles G ; Yeo, Dannel ; Adelstein, Stephen ; Liang, Oliver ; Rasko, John E J ; Sagnella, Sharon M ; Castelletti, Laura ; Chu, Gerard J

BACKGROUND AIMSSeveral anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy.METHODSMSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry. In parallel, the cytotoxicity and specificity of two anti-MSLN CAR T cells (m912 and SS1) were compared against these cell lines using a real-time impedance-based assay. The effect of two MSLN 'sheddase' inhibitors (lanabecestat and TMI-1) that increase MSLN surface expression was also tested in combination with CAR T cells.RESULTSSS1 CAR T cells were more cytotoxic compared with m912 CAR T cells against cell lines that expressed fewer than ∼170 000 MSLN molecules/cell. A comparison of the m912 and amatuximab (humanized SS1) antibodies identified that amatuximab could detect and bind to lower levels of MSLN on pancreatic cancer and mesothelioma cell lines, suggesting that superior antibody/scFv affinity was the reason for the SS1 CAR's superior cytotoxicity. The cytotoxicity of m912 CAR T cells was improved in the presence of sheddase inhibitors, which increased MSLN antigen density.CONCLUSIONSThese data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN.

01 Feb 2024·iScience

Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance

Article

Author: Lim, Sumi ; Özcan, Güliz Gürel ; Kundu, Tanushree ; Donnelly, Joshua ; Rihel, Jason ; Canning, Thomas ; Tirathdas, Lavitasha

Amyloid precursor protein (APP) is a brain-rich, single pass transmembrane protein that is proteolytically processed into multiple products, including amyloid-beta (Aβ), a major driver of Alzheimer disease (AD). Although both overexpression of APP and exogenously delivered Aβ lead to changes in sleep, whether APP processing plays an endogenous role in regulating sleep is unknown. Here, we demonstrate that APP processing into Aβ40 and Aβ42 is conserved in zebrafish and then describe sleep/wake phenotypes in loss-of-function appa and appb mutants. Larvae with mutations in appa had reduced waking activity, whereas larvae that lacked appb had shortened sleep bout durations at night. Treatment with the γ-secretase inhibitor DAPT also shortened night sleep bouts, whereas the BACE-1 inhibitor lanabecestat lengthened sleep bouts. Intraventricular injection of P3 also shortened night sleep bouts, suggesting that the proper balance of Appb proteolytic processing is required for normal sleep maintenance in zebrafish.

05 May 2023·The Journal of organic chemistry

Copper-Catalyzed Racemization-Recycle of a Quaternary Center and Optimization Using a Combined Kinetics-DoE/MLR Modeling Approach.

Article

Author: Morrison, James A. ; Cox, Robert J. ; Munday, Rachel H. ; Taylor, Brian A. ; McCreanor, Niall G.

The copper-catalyzed racemization of a complex, quaternary center of a key intermediate on route to lanabecestat has been identified. Optimization and mechanistic understanding were achieved through the use of an efficient, combined kinetic-multiple linear regression approach to experimental design and modeling. The use of a definitive screening design with mechanistically relevant factors and a mixture of fitted kinetic descriptors and empirical measurements facilitated the generation of a model that accurately predicted complex reaction time course behavior. The synergistic model was used to minimize the formation of dimer byproducts, determine optimal conditions for batch operation, and highlight superheated conditions that could be accessed in flow, leading to a further increase in yield which was predicted by the original model.

100 Deals associated with Lanabecestat

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External Link

KEGG	Wiki	ATC	Drug Bank
D10946	Lanabecestat	-	DB14814

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Liver Diseases	Preclinical	US	Eli Lilly & Co.	01 Jun 2018
Liver Diseases	Preclinical	US	AstraZeneca PLC	01 Jun 2018
Alzheimer Disease	Preclinical	TW	AstraZeneca PLC	01 Jul 2016
Thrombosis	Discovery	US	AstraZeneca PLC	30 Sep 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02245737 (AMARANTH, CTgov)	Phase 2/3	Alzheimer Disease	2,218	Placebo (Placebo)	rkptfxfqfg(emxxrxlttu) = xlehcavnwa jifdgganye (qbodmcqurr, yfjjybfavg - ykhthizirt) View more	-	06 Aug 2019
				Lanabecestat (Lanabecestat 50 mg)	rkptfxfqfg(emxxrxlttu) = bvyncctexh jifdgganye (qbodmcqurr, jhgjtwdujz - lckqzquell) View more
NCT02783573 (DAYBREAK-ALZ, CTgov)	Phase 3	Alzheimer Disease	1,722	Lanabecestat	khzebhzyhx(cccywjdote) = pvspxckzyf ubzhovyeln (vbhwytmqmn, nmzmrblhve - szrcfoswnm) View more	-	06 Aug 2019
NCT02972658 (CTgov)	Phase 3	Alzheimer Disease	421	Lanabecestat (AZES Placebo/AZFD Lanabecestat 20 mg)	tcbfqbrqna(nbgxdbujak) = ucdthjibia mxiejvahwf (zftayzkjel, bekrzqjggq - eyisslnojp) View more	-	05 Jul 2019
				Lanabecestat (AZES Placebo/AZFD Lanabecestat 50 mg)	tcbfqbrqna(nbgxdbujak) = rvmqetmnwf mxiejvahwf (zftayzkjel, vaqlptffzg - nsdgypeeko) View more
NCT02406261 (CTgov)	Phase 1	-	82	simvastatin+Midazolam+Lanabecestat (Cohort A)	meyjsdogqb(ypzythohpl) = fcrdxkuwuf civdmfsohv (ytaxwanelm, hvuugnypev - amprvphcqc) View more	-	22 Mar 2019
				Lanabecestat+Donepezil (Cohort B)	mvahrjxhdu(pkwgcjmziq) = mjenywalvp fwdfzlkowe (urqhethrgv, vvotgdxdap - mmdotcgnwa) View more
NCT03222427 (CTgov)	Phase 1	-	8	LY3314814 (LY3314814)	iaracmgadi(huatactmhf) = jupudblvdq cuttdtttsz (aqupezodrv, immduixsbr - wlxmhllbja) View more	-	22 Mar 2019
				[13C415N3] LY3314814 ([13C415N3] LY3314814)	iaracmgadi(huatactmhf) = kobpebzpnw cuttdtttsz (aqupezodrv, cgvngythzw - agjvebijmn) View more
NCT02245737 (AAIC2016)	Phase 2/3	Alzheimer Disease	84	AZD3293	buubvmcdrc(zgyssnxdur) = ratsncorfz bydcepszrb (lamnrznlru ) View more	-	01 Jul 2016