Delving into the Latest Updates on Elacridar with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Elacridar hydrochloride (USAN)

+ [6]

Target

ABCG2 x P-gp

Mechanism

ABCG2 inhibitors(Broad substrate specificity ATP-binding cassette transporter ABCG2 inhibitors), P-gp inhibitors(P-glycoprotein 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

Chiba University

Inactive Organization

GSK Plc

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC34H33N3O5

InChIKeyOSFCMRGOZNQUSW-UHFFFAOYSA-N

CAS Registry143664-11-3

Amyotrophic lateral sclerosis (ALS) presents a substantial challenge due to its complex nature, limited effective treatment options, and modest benefits from current therapies in slowing disease progression. This study explores the potential of intranasal (IN) delivery to enhance the CNS delivery of riluzole (RLZ), a standard ALS treatment which is subject to blood-brain barrier efflux mechanisms. Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. To quantify RLZ in vivo in mice, [¹⁴C]-RLZ was synthesised using an optimised one-pot method. [¹⁴C]-RLZ yield was 21.3 ± 3.4 %, measured by High Performance Liquid Chromatography (HPLC), with a specific activity of 40.4 ± 3.9 µCi/mg measured by HPLC and liquid scintillation counting. RLZ synthesis was verified using proton nuclear magnetic resonance (¹H NMR), and liquid chromatography-mass spectrometry. IN RLZ (5 mg/kg) produced double the maximum brain levels (1.11 ± 0.34 % Injected Dose (ID)/brain) at 30 min as oral RLZ (5 mg/kg). The uptake of RLZ in the liver was reduced by half for intranasal administration compared to oral administration. Intravenous ELC (5 mg/kg) substantially increased brain levels of IN RLZ to 3.52 ± 0.62 % ID/g brain at 60 min post-administration, compared to 1.87 ± 0.33 % ID/g brain in the absence of the efflux pump inhibitor. However, increased concentrations were also observed in the liver and blood. These results indicate that intranasal delivery of RLZ enhances brain targeting and reduces liver accumulation compared to the oral route. Brain uptake of IN RLZ was enhanced further by ELC, although not selectively as accumulation in the liver or blood was also observed. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of IN RLZ and IN RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development.

20 Oct 2024·Journal of Drug Targeting

An all-in-one nanoparticle for overcoming drug resistance: doxorubicin and elacridar co-loaded folate receptor targeted PLGA/MSN hybrid nanoparticles

Article

Author: Tonbul, Hayrettin ; Öztürk, Süleyman Can ; Tavukçuoğlu, Ece ; Şahin, Adem ; Esendağlı, Güneş ; Akbaş, Sedenay ; Çapan, Yılmaz ; Aktaş, Yeşim ; Ultav, Gözde

Overexpression of permeability-glycoprotein (P-gp) transporter leads to multidrug resistance (MDR) through cellular exclusion of chemotherapeutics. Co-administration of P-gp inhibitors and chemotherapeutics is a promising approach for improving the efficacy of therapy. Nevertheless, problems in pharmacokinetics, toxicity and solubility limit the application of P-gp inhibitors. Herein, we developed a novel all-in-one hybrid nanoparticle system to overcome MDR in doxorubicin (DOX)-resistant breast cancer. First, folic acid-modified DOX-loaded mesoporous silica nanoparticles (MSNs) were prepared and then loaded into PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles along with a P-gp inhibitor, elacridar. This hybrid nanoparticle system had high drug loading capacity, enabled both passive and active targeting of tumour tissues, and exhibited sequential and pH-triggered release of drugs. In vitro and in vivo studies in DOX-resistant breast cancer demonstrated the ability of the hybrid nanoparticles to reverse P-gp-mediated drug resistance. The nanoparticles were efficiently taken up by the breast cancer cells and delivered elacridar, in vitro. Biodistribution studies demonstrated substantial accumulation of the folate receptor-targeted PLGA/MSN hybrid nanoparticles in tumour-bearing mice. Moreover, deceleration of the tumour growth was remarkable in the animals administered with the DOX and elacridar co-loaded hybrid nanoparticles when compared to those treated with the marketed liposomal DOX (Caelyx^®) or its combination with elacridar.

20 Oct 2024·Xenobiotica

The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice

Article

Author: Tang, Ke ; Fu, Min ; Wu, Yu ; Wang, Jin ; Xie, Hong-Guang ; Jiang, Li-Ping ; Li, Hao-Dong ; Ji, Jin-Zi ; Ding, Pei-Jie ; Li, Xue-Mei ; Tai, Ting ; Mi, Qiong-Yu ; Zheng, Zhao-Dong ; Shao, Yuan-Yuan

This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.

100 Deals associated with Elacridar

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External Link

KEGG	Wiki	ATC	Drug Bank
D03968	-	-	DB04881

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	GSK Plc	-
Neoplasms	Preclinical	-	-	-
Neoplasms	Preclinical	US	-	-
Neoplasms	Preclinical	CA	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


P10.21.A (EANO2023)	Not Applicable	Brain Cancer	-	Elacridar	qlnekkqzbp(zelatrvomq) = oxmymlecdw dzerhidfwe (vdzmpgmlnr )	-	08 Sep 2023
EANM2016	Not Applicable	P-glycoprotein	3	Elacridar	xidklneulc(fnsqsnxqtd) = dakgzdzvfv zfsvovqppn (ynsczeezjs )	Positive	21 Sep 2016
EANM2016	Not Applicable	P-glycoprotein	3	High-dose Erlotinib	xidklneulc(fnsqsnxqtd) = jfwlnqelob zfsvovqppn (ynsczeezjs )	Positive	21 Sep 2016
SNMMI2016	Not Applicable	-	-	High dose erlotinib	uuzwtynsoi(jzioedhbjp) = alwhxnwgpp rvlujfpebh (vyiljnnett, 0.03)	-	24 May 2016
SNMMI2016	Not Applicable	-	-	Elacridar	uuzwtynsoi(jzioedhbjp) = yjnswqssny rvlujfpebh (vyiljnnett, 0.35)	-	24 May 2016
ASCO2004	Phase 1	Advanced cancer	23	Topotecan 2 mg + Elacridar 100 mg	ixqmxmhyjw(dhpxbumdin) = DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. xrfzmhzkoa (tyzagmqpko ) View more	-	15 Jul 2004