Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents

Pfister, Jürg R.; Makra, F.; Muehldorf, A. V.; Wu, Hsiao-Hua; Nelson, J.T.; Cheung, Peter Chi Keung; Bruno, Nicholas A.; Casey, Sharon; Zutshi, Neha; Slate, Doris L.

doi:10.1016/0960-894x(95)00426-t

Cited by 32 publications

(27 citation statements)

References 16 publications

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“…Cimetidine and dipyridamole were purchased from Sigma-Aldrich (St. Louis, MO 3 H]colchicine (80.4 Ci/mmol) were purchased from PerkinElmer Life and Analytical Sciences (Waltham, MA). LSN335984 is a dichloro homolog of the difluoro-containing zosuquidar (LY335979), which was developed as a third-generation, specific inhibitor of P-gp (Pfister et al, 1995;Yasuno et al, 2008). All of the other chemicals were commercially available and of reagent grade.…”

Section: Methodsmentioning

confidence: 99%

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Zhao¹,

Raub²,

Sawada³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Expression of breast cancer resistance protein (Bcrp) at the bloodbrain barrier (BBB) has been revealed recently. To investigate comprehensively the potential role of Bcrp at the murine BBB, a chemically diverse set of model compounds (cimetidine, alfuzosin, dipyridamole, and LY2228820) was evaluated using a multiexperimental design. Bcrp1 stably transfected MDCKII cell monolayer transport studies demonstrated that each compound had affinity for Bcrp and that polarized transport by Bcrp was abolished completely by the Bcrp inhibitor chrysin. However, none of the compounds differed in brain uptake between Bcrp wild-type and knockout mice under either an in situ brain perfusion or a 24-h subcutaneous osmotic minipump continuous infusion experimental paradigm. In addition, alfuzosin and dipyridamole were shown to undergo transport by P-glycoprotein (P-gp) in an MDCKII-MDR1 cell monolayer model. Alfuzosin brain uptake was 4-fold higher in mdr1a(؊/؊) mice than in mdr1a(؉/؉) mice in in situ and in vivo studies, demonstrating for the first time that it undergoes P-gpmediated efflux at the BBB. In contrast, P-gp had no effect on dipyridamole brain penetration in situ or in vivo. In fact, in situ BBB permeability of these solutes appeared to be primarily dependent on their lipophilicity in the absence of efflux transport, and in situ brain uptake clearance correlated with the intrinsic transcellular passive permeability from in vitro transport and cellular accumulation studies. In summary, Bcrp mediates in vitro transport of various compounds, but seems to play a minimal role at the BBB in vivo.The blood-brain barrier (BBB) is composed of brain capillary endothelial cells, which are characterized by highly developed tight junctions, a lack of fenestrations, and a paucity of pinocytic and transcytotic activities. Expression of metabolic enzymes and efflux transporters in these and associated glial cells provides additional limiting factors at the BBB. Insufficient drug exposure at the pharmacologic target within the brain, as a consequence of limited flux from blood to brain, represents a major obstacle for effective treatment of central nervous system (CNS) disorders (Begley, 2004;Pardridge, 2005). It is widely accepted that P-glycoprotein (P-gp) is expressed abundantly at the BBB and functions as an efflux pump that extrudes toxic substances and therapeutic agents in the brain-to-blood direction, representing a functional barrier to brain uptake (Schinkel, 1999). The potential role of other members of the ATP-binding cassette (ABC) efflux transporter family, such as multidrug resistance-associated proteins (Mrps) and breast cancer resistance protein (Bcrp), at the BBB is less clear, although the proteins appear to be expressed at the BBB in various species (Yousif et al., 2007).Bcrp is a recently identified member of the ABC efflux transporter family encoded by gene Abcg2 (Doyle et al., 1998). Bcrp is widely expressed in the intestine, liver, mammary gland, and placenta. The functional efficiency of Bcrp in the...

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Section: Methodsmentioning

confidence: 99%

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Zhao¹,

Raub²,

Sawada³

et al. 2009

Drug Metab Dispos

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“…48 Due to the considerable similarity between the active sites of flavindependent LSD1 and MAO enzymes, Johnson and coworkers 49 ~3 h) as shown in Figure 10. 52 However, further development of 23 was discontinued due to toxicity and insufficient inhibition of P-gp.…”

Section: Poly(adp-ribose)polymerase (Parp) Inhibitor 20 (Olaparib/lynmentioning

confidence: 99%

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

2016

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Recently, there has been an increasing use of the cyclopropyl ring in drug development to transition drug candidates from the preclinical to clinical stage. Important features of the cyclopropane ring are, the (1) coplanarity of the three carbon atoms, (2) relatively shorter (1.51 Å) C-C bonds, (3) enhanced π-character of C-C bonds, and (4) C-H bonds are shorter and stronger than those in alkanes. The present review will focus on the contributions that a cyclopropyl ring makes to the properties of drugs containing it. Consequently, the cyclopropyl ring addresses multiple roadblocks that can occur during drug discovery such as (a) enhancing potency, (b) reducing off-target effects,

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“…Eli Lilly provided (2R)-anti-5-f3-[4-(10, 11-dichloromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxygquinoline trihydrochloride (DCPQ), which is a potent inhibitor of P-gp. DCPQ was previously reported as compound 14b (14). Xenova Group, Ltd., provided tariquidar, previously called XR9576 (15).…”

Section: Methodsmentioning

confidence: 99%

¹¹C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux

Zoghbi¹,

Liow²,

Yasuno³

et al. 2008

J Nucl Med

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Loperamide, an opiate receptor agonist, does not cross the blood-brain barrier because it is a substrate for the permeabilityglycoprotein (P-gp) efflux pump. We evaluated 11 C-loperamide as a PET radiotracer to measure P-gp function in vivo. Methods: Monkeys were injected with 11 C-loperamide, and PET brain images were acquired for 120 min. The baseline scans were followed by scans acquired after administration of either of 2 P-gp inhibitors, (2R)-anti-5-f3-[4-(10,11-dichloromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxygquinoline trihydrochloride (DCPQ) or tariquidar. Both the PET scans and ex vivo measurements were obtained in P-gp knockout and wildtype mice. Results: Pharmacologic inhibition of P-gp in monkeys dose-dependently increased brain activity, with a 3.7-fold effect at the highest DCPQ dose (8 mg/kg intravenously). This increase of brain activity was not caused peripherally, because DCPQ insignificantly changed the plasma concentration and plasma protein binding of radiotracer. Furthermore, the structurally dissimilar inhibitor, tariquidar, also increased brain uptake with potency equal to that of DCPQ. P-gp knockout mice had 3-fold higher brain activity on PET than did wild-type animals. Four radiometabolites were detected in the plasma and brains of ex vivo mice. The most lipophilic radiometabolite was found to be comobile with reference dLop on high-performance liquid chromatography. The brain concentrations of 11 C-loperamide and the putative 11 C-dLop were about 16-fold greater in P-gp knockout mice than in wild-type mice. Conclusion: Both 11 C-loperamide and its putative radiometabolite 11 C-dLop are avid P-gp substrates. 11 C-dLop may be superior to 11 C-loperamide in measuring P-gp function at the blood-brain barrier, because further demethylation of 11 CdLop will generate radiometabolites that have little entry into the brain.

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Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents

Cited by 32 publications

References 16 publications

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

¹¹C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux

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Methanodibenzosuberylpiperazines as potent multidrug resistance reversal agents

Cited by 32 publications

References 16 publications

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier

The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules

11C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux

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¹¹C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux