Delving into the Latest Updates on Timcodar dimesilate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Timcodar, Timcodar dimesylate

+ [1]

Target

P-gp

Mechanism

P-gp inhibitors(P-glycoprotein 1 inhibitors)

Therapeutic Areas

NeoplasmsNervous System DiseasesEndocrinology and Metabolic Disease+ [1]

Active Indication-

Inactive Indication

Bacterial InfectionsDiabetic NeuropathiesRelapsed Solid Neoplasm+ [1]

Originator Organization

Vertex Pharmaceuticals, Inc.

Active Organization-

Inactive Organization

Vertex Pharmaceuticals, Inc.

National Cancer Institute

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC43H45ClN4O6

InChIKeyMQSMWZHHUGSULF-QNGWXLTQSA-N

CAS Registry179033-51-3

View All Structures (2)

Current treatment for tuberculosis (TB) is complicated by the emergence of multidrug resistant TB (MDR-TB). As a result, there is an urgent need for new powerful anti-TB regimens and novel strategies. In this study, we aimed to potentiate a moxifloxacin + linezolid backbone as treatment for MDR-TB with the efflux pump inhibitors verapamil and timcodar as well as with drugs that act on mycobacterial cell wall stability such as colistin and SQ109. Using a time-kill kinetics assay, the activities of moxifloxacin, linezolid, verapamil, timcodar, colistin and SQ109 as single drugs against Mycobacterium tuberculosis were evaluated. In addition, the activity of the moxifloxacin + linezolid backbone in combination with one of the potentiator drugs was assessed. As little as 0.125 mg/L moxifloxacin achieved 99% killing of M. tuberculosis after 6 days of exposure. Linezolid showed moderate killing but 99% killing was not achieved. Verapamil, timcodar and colistin only resulted in killing with the highest concentrations tested but 99% killing was not achieved. SQ109 resulted in complete elimination after 1 day of exposure to 256 mg/L and in 99% elimination after 6 days of exposure to 1 mg/L. Furthermore, colistin added to the moxifloxacin + linezolid backbone resulted in increased elimination, whereas verapamil, timcodar and SQ109 showed no added value to the backbone. This finding that colistin potentiates the activity of the moxifloxacin + linezolid backbone against M. tuberculosis suggests its potential role in further studies on the applicability of a moxifloxacin + linezolid treatment of MDR-TB.

01 Jan 2016·TuberculosisQ3 · MEDICINE

Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters

Q3 · MEDICINE

Article

Author: Aarnoutse, Rob E ; Burger, David M ; Koenderink, Jan B ; Te Brake, Lindsey H M ; de Knegt, Gerjo J ; van den Heuvel, Jeroen J M W ; Russel, Frans G M ; de Steenwinkel, Jurriaan E

BACKGROUNDMultiple-drug therapy for tuberculosis (TB) and TB-associated co-morbidity increase the likelihood of drug-drug interactions (DDIs). Inhibition of membrane transporters is an important mechanism underlying DDIs. In this study, we assessed the in vitro inhibitory potential of currently used first and second-line TB drugs and of proposed mycobacterial efflux pump inhibitors (EPIs) on the major ABC transporters relevant to drug transport, namely P-gp, BCRP, BSEP and MRP1-5.METHODSMembrane vesicles isolated from transporter-overexpressing HEK293 cells were used to study the inhibitory action of TB drugs and EPIs on the transport of model substrates [(3)H]-NMQ (P-gp); [(3)H]-E1S (BCRP); [(3)H]-TCA (BSEP); [(3)H]-E217βG (MRP1, 3 and 4) and [(3)H]-MTX (MRP2 and 5).RESULTSA strong inhibition (IC50 value <15 μM) was observed for clofazimine (P-gp, BCRP and MRP1), thioridazine (BCRP), timcodar (P-gp, BSEP and MRP1) and SQ109 (P-gp and BCRP). Rifampicin inhibited all transporters, but less potently.CONCLUSIONSCo-administration of clofazimine, thioridazine, timcodar, SQ109 and possibly rifampicin with drugs that are substrates for the inhibited transporters may lead to DDIs. The mycobacterial EPIs potently inhibited a wider range of human ABC transporters than previously reported. These vesicular transport data are especially valuable considering the current emphasis on development of TB drug regimens.

01 Jan 2016·PPAR ResearchQ3 · MEDICINE

Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγand Suppresses Adipogenesis

Q3 · MEDICINE

ArticleOA

Author: Hinds, Terry D. ; McBeth, Lucien ; Trabbic, Christopher J. ; Sanchez, Edwin R. ; John, Kezia

Nutrient overload and genetic factors have led to a worldwide epidemic of obesity that is the underlying cause of diabetes, atherosclerosis, and cardiovascular disease. In this study, we used macrolide drugs such as FK506, rapamycin, and macrolide derived, timcodar (VX-853), to determine their effects on lipid accumulation during adipogenesis. Rapamycin and FK506 bind to FK506-binding proteins (FKBPs), such as FKBP12, which causes suppression of the immune system and inhibition of mTOR. Rapamycin has been previously reported to inhibit the adipogenic process and lipid accumulation. However, rapamycin treatment in rodents caused immune suppression and glucose resistance, even though the mice lost weight. Here we show that timcodar (1 μM), a non-FKBP12-binding drug, significantly (p<0.001) inhibited lipid accumulation during adipogenesis. A comparison of the same concentration of timcodar (1 μM) and rapamycin (1 μM) showed that both are inhibitors of lipid accumulation during adipogenesis. Importantly, timcodar potently (p<0.01) suppressed transcriptional regulators of adipogenesis, PPARγand C/EBPα, resulting in the inhibition of genes involved in lipid accumulation. These studies set the stage for timcodar as a possible antiobesity therapy, which is rapidly emerging as a pandemic.

100 Deals associated with Timcodar dimesilate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12761

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Relapsed Solid Neoplasm	Phase 2	US	National Cancer Institute	01 Mar 1996
Bacterial Infections	Phase 2	US	Vertex Pharmaceuticals, Inc.	-
Diabetic Neuropathies	Phase 2	US	Vertex Pharmaceuticals, Inc.	-
Solid tumor	Phase 2	US	Vertex Pharmaceuticals, Inc.	-