Progress in research on efflux pump inhibitors continues

2021-03-27 12:04:15

With the development of antibiotics and chemotherapy drugs and their wide application in clinic, bacteria and tumor cells also have a variety of drug resistance, of which active efflux is one of the main mechanisms. Overexpression of efflux pump drug excretion increased, the drug concentration in the cell body decreased, clinical efficacy decreased or ineffective. The efflux pump inhibitor can not only inhibit drug efflux of drug-resistant bacteria and tumor cells, restore its sensitivity to drugs, improve the clinical efficacy of drug-resistant bacteria and tumors, but also improve the pharmacokinetics of some drugs (Such as improving the absorption of oral drugs, reducing liver and kidney clearance) also has a wide range of uses. In recent years, efflux pump inhibitors made great progress. ATP hydrolysis can drive new products frequently appear According to the drug efflux mechanism is different, active efflux system can be divided into ATP hydrolysis driven efflux pump and transmembrane proton gradient can drive efflux pump two categories. A common feature of ATP-hydrolyzate-driven efflux pump inhibitors is their reversal of activity by inhibiting ATP-binding membrane glycoproteins. According to the specificity of the inhibitor binding to the membrane glycoprotein and the affinity, the current ATP hydrolysis-driven efflux pump inhibitors have been three generations of products appear. The first generation of inhibitors such efflux pump inhibitors and membrane glycoprotein binding specificity and affinity is not high in the clinical indications, and the high dose, side effects, and thus in clinical Application is limited. On behalf of the drug reserpine, verapamil, cyclosporin A (CsA), tamoxifen and toremifen and so on. Verapamil was found to be an early multidrug resistance reversal agent, but its reversal activity is not strong, due to the cardiovascular system adverse reaction limits its clinical application. Foreign researchers on the tetraoxodithiane and ditiarane verapamil derivatives were studied found that these two compounds in the presence of glutathione, some compounds such as RO11-3651 and RO11-2751 showed strong ; The tetraoxodithioxane verapamil derivatives (except RO11-3651) were inactive and the structural modifications at other positions did not improve their efflux, indicating that the tetraoxodithianyl It may not be beneficial for compounds to interact with multidrug resistance-associated protein 1 (MRP1). The size of liposoluble may be the most important factor affecting the inhibition of MRP1 activity by these two classes of compounds. Topiramate and tamoxifen are trityl estrogen antagonists. Tamoxifen has a stronger reversal activity than toremiphene, but its in vivo tolerance is poor. Studies have shown that short-term, high-dose torethromycin combined with vincristine is well tolerated and can effectively reverse multidrug resistance (MDR) in tumors. Second Generation Inhibitors Representatives of such inhibitors include PSC833 (Valspodar), VX-710 (biricodar, incel), MS-209, GF120918 and dexverapamil. PSC833 is a derivative of cyclosporin D with a higher activity than CsA and without the immunosuppressive effect of CsA. PSC833 combined with mitoxantrone, etoposide and Cytarabine in the treatment of acute myeloid leukemia was evaluated in a multicenter phase II clinical trial. VX-710, a piperidine derivative, is a broad-spectrum efflux pump inhibitor that inhibits P-glycoprotein (P-gp) and MRP1 simultaneously. The results of phase II evaluation of combination of VX-710 and paclitaxel in the treatment of resistant ovarian cancer suggest that it can restore the sensitivity of resistant tumors to paclitaxel with good safety and tolerability. MS-209 is a novel quinoline derivative that can be used in combination with chemotherapeutic agents to reverse drug-resistant small cell lung cancer (SCLC) resistance and to inhibit its multi-tissue metastases. GF120918 is a synthetic acridine inhibitor of P-gp-mediated multidrug resistance. GF120918 and doxorubicin combined treatment of solid tumors in a clinical study and pharmacological studies have shown that: both in vitro and in vivo tests, they can inhibit P-gp, and less side effects. Compared with the first generation, these inhibitors have higher membrane glycoprotein affinity, and do not have the pharmacological activity of the first generation of inhibitors, but can cause complex drug interactions in the clinical Application still needs further study. Third-generation inhibitors Compared with the first two generations of inhibitors, these inhibitors have higher inhibitory activity and selectivity, and overcome the shortcomings of second-generation inhibitors and drug interactions without affecting the kinetic properties of the drugs The clinical application of broad prospects. At present, the drugs under study are LY335979, XR9576 and OC144-093 and so on. LY335979 quinoline derivatives, is an efficient and highly selective P-gp inhibitor. It has a high affinity for P-gp but is not a substrate for P-gp, does not inhibit MRP at concentrations that inhibit P-gp, and phase I clinical trials with doxorubicin in the treatment of advanced malignancies have been completed. XR9576 is an anthranilic acid derivative that specifically inhibits P-gp. Both oral and intravenous administration, which can exert a sustained inhibitory effect, and well tolerated, has passed a clinical evaluation of safety. OC144-093 is a new imidazole compound that has no cytotoxicity per se and can reverse drug resistance of doxorubicin and vincristine to drug-resistant cancer cells at low doses. Foreign studies found that: the two substituents in the weak acid (COOH) or neutral (OH) substituents as active essential groups; N-1 position of the substituent group is not conducive to enhancing MDR inhibition, but also affect the C -5-position benzene ring space conformation; imidazole C-4 position of benzene ring para-substituent size also affect the compound on MDR activity. Surfactants are a special class of P-gp inhibitors that alter the secondary and tertiary structures of P-gp, rendering them inactive. Surfactants such as polyethylene glycol, Tween 80, and cremophor EL act on the Caco-2 cell membrane, changing their fluidity and making it easier for cells to take drugs, but research on these compounds remains at the experimental stage in vitro . In addition, some scholars have found a variety of natural products that inhibit efflux pump activity from plants, such as green tea polyphenols, alisma albumen, echinacea sesquiterpenoids and so on. Therefore, it is hoped that beneficial structural tips will be obtained. Transmembrane Proton Gradient Driven Type Research Progress In recent years, research on transmembrane proton gradient-driven efflux pump inhibitors has also been progressively in-depth and remarkable progress has been made. The study found that 5 "-MHC (5" -methoxyhydnocarpin) alone without antibacterial activity, but combined with antimicrobial drugs can completely inhibit MDR efflux. There are also studies have shown that: 3-OH substitution may play a role in P-gp inhibition, but not conducive to the inhibition of NorA efflux pump; 7-OH substitution does not affect the inhibitory activity of the compound, but the most active compound A ring There is no -OH substitution; 4-OMe or 4-OH substitution, the fat-soluble changes have little effect on the activity of the compound. Surprisingly, some simple alkylated flavonoids also show potent MDR pump inhibitory activity. MC-207,110 and MC-02,595 are broad-spectrum efflux pump inhibitors of dipeptides. Studies have shown that the inhibitory potency of these compounds is independent of the peptide. As long as the compounds have double cations and have similar liposolubility, they can inhibit the efflux of MDR. Compound Liposolubility is associated with toxicity; ornithine is an important group that affects toxicity. Based on the above studies, foreign researchers replaced ornithine with bioisosomal arginine to synthesize MC-04,124 and its activity was similar to that of MC-02,595, but its toxicity was only 1 / 4.13-CPTC Is a structurally modified tetracycline obtained with a suppression of efflux compounds, the half effective concentration (IC50) value of 0.4 ~ 1.0 micromol / liter. It has a high affinity for the Tet (B) protein and competes with tetracycline for binding to the efflux site. Ro07-3149 competitively inhibited drug-resistant bacterial efflux of tetracycline, increased intracellular tetracycline concentration at 25 mg / l, and reduced tetracycline MIC (MIC) at 8 mg / l . Ro07-3149 structure had been transformed, but found no better compounds. INF392 is one of the compounds with inhibitory activity on NorA screened by Markham et al. From a small molecule library. The IC50 of ciprofloxacin can be reduced to the original at a concentration significantly lower than reserpine (0.6 mg / l) Of 1/2 ~ 1/3. Cyclophenhydrazone (CCCP) is a proton kinetic uncoupler and a new antacid, including rabeprazole, omeprazole, lansoprazole, Inhibit the efflux of proton gradient efflux pump. Active drug efflux systems are involved in drug resistance to clinical treatment inconvenience, and efflux pump inhibitors is expected to become a new drug to restore drug sensitivity and improve clinical efficacy, its application in improving the bioavailability of oral drugs At present, it has become a hot spot in drug research and I believe there will be more excellent efflux pump inhibitors coming out in the near future.

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