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167465-36-3

167465-36-3 structure
167465-36-3 structure
Name Zosuquidar Trihydrochloride
Synonyms (R)-4-[(1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptan-6-yl]-α-[(5-quinoloyloxy)methyl]-1-piperazineethanol trihydrochloride
1-piperazineethanol, 4-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptan-6-yl)-α-1[(5-quinolinyloxy)methyl-, trihydrochloride, [6(R)-(1α,6α,10bα)]-
Zosuquidar Trihydrochloride
1-Piperazineethanol, 4-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-α-[(5-quinolinyloxy)methyl]-, (αR)-, hydrochloride (1:3)
(2R)-1-{4-[(1aR,10bS)-1,1-Difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c][7]annulen-6-yl]-1-piperazinyl}-3-(5-quinolinyloxy)-2-propanol trihydrochloride
LY335979
Zosuquidar 3HCl
Zosuquidar (trihydrochloride)
Description Zosuquidar trihydrochloride is an inhibitor of P-glycoprotein with a Ki value of 59 nM.
Related Catalog
Target

Ki: 59nM (P-glycoprotein)[1].

In Vitro Zosuquidar completely or partially restores drug sensitivity in all P-gp-expressing leukemia cell lines and enhances the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AmL blasts with active P-gp. In addition, P-gp inhibition by zosuquidar is found to be more potent than cyclosporine A in cells with highly active P-gp[2].
In Vivo Zosuquidar trihydrochloride is only moderately active as an inhibitor of P-gp at the blood-brain. An oral dose of 25 mg/kg of zosuquidar trihydrochloride increases the brain concentrations by about 2.5-fold at 1 h and 5-fold at 24 h after paclitaxel administrationbarrier[3]. Zosuquidar enhances the brain uptake of nelfinavir in a dose-dependent manner. Brain tissue/plasma nelfinavir concentration ratios increase from 0.06±0.03 in the absence of zosuquidar administration and 0.09±0.02 between 2 and 6 h after a 2 mg/kg intravenous dose of zosuquidar to 0.85±0.19 after 6h and 1.58±0.67 after 20 mg/kg zosuquidar[4].
Cell Assay Cells are cultured in 96-well plates. Each drug of interest is added at escalating concentrations in the presence or absence of either zosuquidar or CsA. After 48 hour incubation (except Mylotarg, 4 days incubation), 20 μL of MTT is added to each well for a further 4 hour incubation. The purple precipitate is dissolved in 200 μL DMSO, and the optic density (OD) is determined by the multi-well plate reader[2].
Animal Admin Rats: Female Sprague-Dawley rats are used in the study. Zosuquidar solutions are prepared in 5% mannitol and adjusted to pH ～2.0 with concentrated HCl. Nelfinavir is infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h. Brain tissue and plasma are analyzed for both drug concentrations[4]. Mice: A stock solution of 5 mg/mL of zosuquidar trihydrochloride is prepared in vehicle solution and diluted in sterile saline. The vehicle solution consisted of 20 g/l mannitol and 1.5 g/l of glycine in water for injection and adjusted to a pH of 2.7 with hydrochloric acid. P-gp knockout mice and wild type mice are used as a model for complete inhibition of P-gp. Zosuquidar trihydrochloride is administered orally at 25 and 80 mg/kg 1 h before i.v. paclitaxel and i.v. at 20 mg/kg 10 min and 1 h before paclitaxel. The concentrations of paclitaxel in plasma and tissues and of zosuquidar trihydrochloride in plasma are quantified by high-performance liquid chromatography[3].
References

[1]. Cripe LD, et al. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood.?201

[2]. Tang R, et al. Zosuquidar?restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AmL). BMC Cancer.?2008 Feb 13;8:51.?

[3]. Kemper EM, et al. The influence of the P-glycoprotein inhibitor zosuquidar trihydrochloride (LY335979) on the brain penetration of paclitaxel in mice. Cancer Chemother Pharmacol. 2004 Feb;53(2):173-8.

[4]. Anderson BD, et al. Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. Drug Metab Dispos. 2006 Apr;34(4):653-9.

[5]. Hou J, et al. Quantitative determination and pharmacokinetic study of the novel anti-Parkinson's disease candidate drug FLZ in rat brain by high performance liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2012 Jul;66:232-9.
Boiling Point 690.5ºC at 760mmHg
Melting Point 172-176°C
Molecular Formula C32H34Cl3F2N3O2
Molecular Weight 636.987
Flash Point 371.4ºC
Exact Mass 635.168457
PSA 48.83000
LogP 7.49320
Storage condition Hygroscopic, -20?C Freezer, Under Inert Atmosphere
Hazard Codes Xi
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