Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.
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PMID:Anticancer effects of zoledronic acid against human osteosarcoma cells. 1660 11

New pentacyclic inhibitors of the P-glycoprotein carrying nitrogen-containing alkyl chains were synthesized and evaluated for MDR reverting activity on mouse lymphoma cells infected with pHa MDR1/A retrovirus. The activity of the compounds proved to be up to 5-fold higher than verapamil, used as reference compound.
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PMID:New potent P-glycoprotein inhibitors carrying a polycyclic scaffold. 1672 21

Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.
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PMID:In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450. 1690 25

Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency on the P-glycoprotein (P-gp) transporter. Previous studies showed that the replacement of the aromatic spacer group between nitrogen atoms (N(1) and N(2)) in the P-gp inhibitor XR9576 with ethyl or propyl chain is optimal for P-gp inhibition potency. To confirm that observation, the ethyl or the propyl linker arm was replaced with a pyrrolidine or an alicyclic group such as cyclohexyl. In addition, an arylpiperazinyl group and two methoxyl groups onto the anthranilic part were introduced to assess their effect on the anti P-gp activity. Five molecules were prepared and evaluated on CEM/VLB500. All new anthranilamides were more potent than verapamil, most of them exhibited a lower cytotoxicity than XR9576. Compound 5 was the most potent and its inhibition activity was similar to XR9576. Interestingly, in vitro biotransformation studies of compounds 4 and 5 using human CYP-450 isoforms revealed, that conversely to XR9576, compounds 4 and 5 inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of numerous drugs, notably paclitaxel. In that context, 5 might be suitable for further drug development.
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PMID:In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity on CYP-450 (Part 2). 1739 90

P-glycoprotein (P-gp) is an ATP dependent efflux transporter protein that has been demonstrated to play a critical role in affecting the absorption, metabolism, elimination and toxicity (ADMET) characteristics of a large number of marketed drugs. Therefore, it is important to evaluate whether or not compounds of interest are likely to interact with P-gp and/or other efflux transporters. An in silico efflux substrate (potential substrate of P-gp and or other transporters) classification model has been developed based on in vitro bi-directional Caco-2 cell permeability and five descriptors, using 14 marketed drugs and >100 discovery compounds synthesized at Bristol-Myers Squibb PRI. The model suggests that efflux substrates tend to contain electron deficient aromatic rings, are highly branched, and most contain tertiary nitrogen. This model demonstrated approximately 80% predictability of both non-substrates and substrates from a training set of 125 compounds. For a validation set of 46 compounds the predictability was approximately 72% for non-substrates and approximately 89% for substrates. The model has the potential to be used both as a filter for library designs to identify potential efflux substrates in early discovery as well as a primary screening methodology to identify the efflux substrate potential of drug candidates.
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PMID:Development of an in silico model for predicting efflux substrates in Caco-2 cells. 1758 55

Multidrug resistance transporters P-glycoprotein/ABCB1 and ABCG2 limit the effect of a large number of cytostatic and cytotoxic drugs by energy-dependent efflux. In experimental models, pump inhibitors reestablish sensitivity towards these drugs. Both transporters demonstrate remarkably broad and partly overlapping substrate specificity. Propafenone analogues are inhibitors of a large number of drug efflux pumps including P-glycoprotein and ABCG2 as well as the microbial pumps. Here the two human ABC transporters ABCB1 and ABCG2 have been studied with respect to interaction with this class of compounds. Data indicate that within the same chemical scaffold, selectivity indices span three orders of magnitude. Compounds with the highest selectivity indices contain a non-ionizable nitrogen atom. Qualitative and quantitative pharmacophore models indicate that hydrophobicity, the number of rotatable bonds, and the number of H-bond acceptors are key features for both activity and selectivity.
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PMID:Multispecificity of drug transporters: probing inhibitor selectivity for the human drug efflux transporters ABCB1 and ABCG2. 1799 97

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.
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PMID:Kinesin spindle protein (KSP) inhibitors. 9. Discovery of (2S)-4-(2,5-difluorophenyl)-n-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the treatment of taxane-refractory cancer. 1857 72

Cetirizine, marketed as a racemic mixture containing both levocetirizine and dextrocetirizine, is a member of the second generation H(1) antihistamines clinically used for the treatment of symptoms associated with seasonal allergic rhinitis. Recently, its single R-enantiomer levocetirizine has been approved by the FDA as the newest antihistamine. Cetirizine is a piperazine derivative related to the first generation H(1) antagonist hydroxyzine, and is the major metabolite in the blood circulation after hydroxyzine administration in humans. The acid functionality of cetirizine in combination with one of the basic nitrogens of piperazine ring makes this compound a very unique zwitterion. The molecular structure of cetirizine allows its carboxylic group to interact with the basic nitrogen via folded conformers, therefore, it possesses relatively high lipophilicity at physiological pH (LogD=1.5). While both cetirizine and hydroxyzine possess high affinity at the H(1) receptor, the R-configured levocetirizine has much slower dissociation rate from the H(1) receptor than R-hydroxyzine, making it an insurmountable antagonist. In addition, the pharmacokinetics of cetirizine significantly differs from those of the basic and lipophilic hydroxyzine. For example, cetirizine has much lower CNS penetration than hydroxyzine, which may be explained by the zwitterionic structure of cetirizine and its P-glycoprotein activity. Cetirizine exhibits high intestinal absorption in humans and its oral bioavailability is estimated to be greater than 70%. Very importantly, cetirizine, especially levocetirizine, has a negligible interaction with the liver enzymes, and is mainly excreted in the urine as the parent despite its high plasma protein binding (88 approximately 96%). The recommended dose of levocetirizine is 5 mg once daily, while its pharmacokinetic half-life is about 7 h in humans. This review will focus on the physicochemical, pharmacological and pharmacokinetic properties of cetirizine and levocetirizine in comparison with those of hydroxyzine. The zwitterionic cetirizine displays distinct advantages over the basic hydroxyzine in several categories such as slow receptor dissociation rate, high selectivity, negligible liver enzyme interaction and low CNS penetration. Therefore, cetirizine, or its single isomer levocetirizine, might serve a good example for medicinal chemists to design zwitterionic drugs from a basic, acidic or neutral lead molecule for peripheral biological targets.
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PMID:Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine. 1878 43

Four series of aromatic carboxylic acids were prepared with a urea or thiourea moiety at the neighboring position to the carboxyl group and benzene or thiophene as aromatic scaffold. Using a calcein AM assay, these compounds were evaluated as inhibitors of multidrug resistance-associated protein 1 (MRP1) and selected compounds were examined toward P-glycoprotein (P-gp) as well as breast cancer resistance protein (BCRP) to assess selectivity for MRP1. Two 2-thioureidobenzo[b]thiophene-3-carboxylic acids (48, 49) were identified as particularly potent inhibitors of MRP1, with IC50 values of around 1 microM. The structural features of this new family of nontoxic MRP1 inhibitors include a (thio)urea disubstituted with preferentially two alkyl groups at the terminal nitrogen and an additional fused aromatic ring.
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PMID:Aromatic 2-(thio)ureidocarboxylic acids as a new family of modulators of multidrug resistance-associated protein 1: synthesis, biological evaluation, and structure-activity relationships. 1958 Mar 19

A new strategy for assessing cell surface carbohydrates and P-glycoprotein (P-gp) expression status and quantifying the cell numbers with an electrochemical immunoassay was designed. In order to construct the base of the cytosensor, a novel 3-D architecture was initially fabricated by combining nitrogen-doped carbon nanotubes, thionine, and gold nanoparticles via a simple layer-by-layer method. The formed architecture provided an effective matrix for concanavalin A (Con A) binding and made the immobilized Con A hold high stability and bioactivity. On the basis of the specific recognition of cell surface mannosyl groups to Con A, the Con A/3-D architecture interface showed a predominant capability for cell capture. With another coupled signal amplification based on a enzymatic catalytic reaction of HRP toward the oxidation of thionine by the H(2)O(2), which was induced by two-step immunoreactions, the proposed cytosensor showed an excellent analytical performance for the detection of HeLa cells ranging from 8.0 x 10(2) to 2.0 x 10(7) cells mL(-1) with a limit of detection of 500 cells mL(-1). Moreover, with the use of preblocking procedures, the mannosyl groups and P-gp on single HeLa cell could be further detected to be (4 +/- 2) x 10(10) molecules of mannose moieties and 8.47 x 10(6) molecules of P-gp. This strategy offers great promise for sensitive detection of cancer cells and cell surface receptors and thus may help improve cancer diagnosis and treatment.
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PMID:Design and implementation of electrochemical cytosensor for evaluation of cell surface carbohydrate and glycoprotein. 2036 31


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