|
Inhibition of human cytochrome P450 3A4
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
In vitro inhibition of Lanosterol 14-alpha demethylase (Candida albicans CY1005)
|
Candida albicans
|
0.06
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of cyclohexyl analogs of restricticin
Year : 1994
Volume : 4
Issue : 5
First Page : 733
Last Page : 736
Authors : Tsukuda T, Watanabe M, Ontsuka H, Fujimoto Y, Shimma N
|
Inhibition of P-glycoprotein, mouse L-mdr1a expressed in LLC-PK1 epithelial cells using calcein-AM polarisation assay
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Inhibition of P-glycoprotein, mouse L-mdr1b expressed in LLC-PK1 epithelial cells using calcein-AM polarisation assay
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Inhibition of P-glycoprotein using calcein-AM assay transfected in porcine PBCEC
|
None
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
2.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Antagonist activity at hedgehog receptor
|
None
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Modulators of the hedgehog signaling pathway.
Year : 2010
Volume : 18
Issue : 18
First Page : 6613
Last Page : 6624
Authors : Heretsch P, Tzagkaroulaki L, Giannis A.
Abstract : Since its discovery by C. Nüsslein-Volhard and E. F. Wieschaus, hedgehog (hh) signaling has come a long way. Today it is regarded as a key regulator in embryogenesis where it governs processes like cell proliferation, differentiation, and tissue patterning. Furthermore, in adults it is involved in the maintenance of stem cells, and in tissue repair and regeneration. But hh signaling has a second-much darker-face: it plays an important role in several types of human cancers where it promotes growth and enables proliferation of tumor stem cells. The etiology of medulloblastoma and basal cell carcinoma is tightly linked to aberrant hh activity, but also cancers of the prostate, the pancreas, the colon, the breasts, rhabdomyosarcoma, and leukemia, are dependent on irregular hh activity. Recent clinical studies have shown that hh signaling can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology. Thus, modulation of hh signaling by means of small molecules has emerged as a valuable tool in combating these hh-dependent cancers. Cyclopamine, a unique natural product with a fascinating history, was the first identified inhibitor of hh signaling and its story is closely linked to the progress in the whole field. In this review we will trace the story of cyclopamine, give an overview on the biological modes of hh signaling both in untransformed and malignant cells, and finally present potent modulators of the hh pathway-many of them already in clinical studies. For more than 30 years now the knowledge on hh signaling has grown steadily-an end to this development is far from being conceivable.
|
Binding affinity to Candida albicans CYP56 by spectrophotometry
|
Candida albicans
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : CYP56 (Dit2p) in Candida albicans: characterization and investigation of its role in growth and antifungal drug susceptibility.
Year : 2008
Volume : 52
Issue : 10
First Page : 3718
Last Page : 3724
Authors : Melo NR, Moran GP, Warrilow AG, Dudley E, Smith SN, Sullivan DJ, Lamb DC, Kelly DE, Coleman DC, Kelly SL.
Abstract : The complete DNA sequence of Candida albicans DIT2, encoding cytochrome P450 family 56 (CYP56), was obtained, and heterologous expression was achieved in Escherichia coli, where CYP56 was targeted to the membrane fraction. In reconstituted assays with the purified enzyme, CYP56 was shown to catalyze the conversion of N-formyl tyrosine into N,N'-bisformyl dityrosine, a reaction that was dependent on cytochrome P450 reductase, NADPH, and oxygen, yielding a turnover of 21.6 min(-1) and a k(s) of 26 microM. The Hill number was calculated as 1.6, indicating that two molecules of the substrate could bind to the protein. Azole antifungals could bind to the heme of CYP56 as a sixth ligand with high affinity. Both chromosomal alleles of CYP56 were disrupted using the SAT1 flipper technique, and CYP56 was found to be nonessential for cell viability under the culture conditions investigated. Susceptibility to azole drugs that bind to cytochromes P450 was tested, and the mutant showed unaltered susceptibility. However, the mutant showed increased susceptibility to the echinocandin drug caspofungin, suggesting an alteration in 1,3-glucan synthase and/or cell wall structure mediated by the presence of dityrosine. Phenotypically, the wild-type and mutant strains were morphologically similar when cultured in rich yeast extract-peptone-dextrose medium. However in minimal medium, the cyp56Delta mutant strain exhibited hyphal growth, in contrast to the wild-type strain, which grew solely in the yeast form. Furthermore, CYP56 was essential for chlamydospore formation.
|
PUBCHEM_BIOASSAY: Luminescence Cell-Based/Microorganism Dose Confirmation HTS to Identify Inhibitors of Trypanosoma cruzi Replication. (Class of assay: confirmatory) [Related pubchem assays: 1885, 1968 ]
|
None
|
100.0
nM
|
|
Title : PubChem BioAssay data set
|
Binding affinity to Mycobacterium smegmatis ATCC 700084 CYP164A2 at pH7.5
|
Mycobacterium smegmatis
|
780.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Identification, characterization, and azole-binding properties of Mycobacterium smegmatis CYP164A2, a homolog of ML2088, the sole cytochrome P450 gene of Mycobacterium leprae.
Year : 2009
Volume : 53
Issue : 3
First Page : 1157
Last Page : 1164
Authors : Warrilow AG, Jackson CJ, Parker JE, Marczylo TH, Kelly DE, Lamb DC, Kelly SL.
Abstract : The genome sequence of Mycobacterium leprae revealed a single open reading frame, ML2088 (CYP164A1), encoding a putative full-length cytochrome P450 monooxygenase and 12 pseudogenes. We have identified a homolog of ML2088 in Mycobacterium smegmatis and report here the cloning, expression, purification, and azole-binding characteristics of this cytochrome P450 (CYP164A2). CYP164A2 is 1,245 bp long and encodes a protein of 414 amino acids and molecular mass of 45 kDa. CYP164A2 has 60% identity with Mycobacterium leprae CYP161A1 and 66 to 69% identity with eight other mycobacterial CYP164A1 homologs, with three identified highly conserved motifs. Recombinant CYP164A2 has the typical spectral characteristics of a cytochrome P450 monooxygenase, predominantly in the ferric low-spin state. Unusually, the spin state was readily modulated by increasing ionic strength at pH 7.5, with 50% high-spin occupancy achieved with 0.14 M NaCl. CYP164A2 bound clotrimazole, econazole, and miconazole strongly (K(d), 1.2 to 2.5 muM); however, strong binding with itraconazole, ketoconazole, and voriconazole was only observed in the presence of 0.5 M NaCl. Fluconazole did not bind to CYP164A2 at pH 7.5 and no discernible type II binding spectrum was observed.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton mentagrophytes B70554 by resazurin based fluorimetry assay
|
Trichophyton mentagrophytes
|
370.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton rubrum B68183 by resazurin based fluorimetry assay
|
Trichophyton rubrum
|
560.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Trichophyton rubrum J941704 by resazurin based fluorimetry assay
|
Trichophyton rubrum
|
980.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Antifungal activity against 5 x 10'6 CFU/ml Candida kefyr B46120 by resazurin based fluorimetry assay
|
Kluyveromyces marxianus
|
400.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro profiling of pramiconazole and in vivo evaluation in Microsporum canis dermatitis and Candida albicans vaginitis laboratory models.
Year : 2010
Volume : 54
Issue : 11
First Page : 4927
Last Page : 4929
Authors : de Wit K, Paulussen C, Matheeussen A, van Rossem K, Cos P, Maes L.
Abstract : The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC₅₀], 0.04 to 1.83 μM) and Microsporum and Trichophyton spp. (IC₅₀, 0.15 to 1.34 μM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
|
Binding affinity to Aspergillus fumigatus AF293 sterol 14-alpha demethylase isoenzyme B expressed in Escherichia coli assessed as tight binding affinity constant
|
Aspergillus fumigatus
|
31.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Expression, purification, and characterization of Aspergillus fumigatus sterol 14-alpha demethylase (CYP51) isoenzymes A and B.
Year : 2010
Volume : 54
Issue : 10
First Page : 4225
Last Page : 4234
Authors : Warrilow AG, Melo N, Martel CM, Parker JE, Nes WD, Kelly SL, Kelly DE.
Abstract : Aspergillus fumigatus sterol 14-α demethylase (CYP51) isoenzymes A (AF51A) and B (AF51B) were expressed in Escherichia coli and purified. The dithionite-reduced CO-P450 complex for AF51A was unstable, rapidly denaturing to inactive P420, in marked contrast to AF51B, where the CO-P450 complex was stable. Type I substrate binding spectra were obtained with purified AF51B using lanosterol (K(s), 8.6 μM) and eburicol (K(s), 22.6 μM). Membrane suspensions of AF51A bound to both lanosterol (K(s), 3.1 μM) and eburicol (K(s), 4.1 μM). The binding of azoles, with the exception of fluconazole, to AF51B was tight, with the K(d) (dissociation constant) values for clotrimazole, itraconazole, posaconazole, and voriconazole being 0.21, 0.06, 0.12, and 0.42 μM, respectively, in comparison with a K(d) value of 4 μM for fluconazole. Characteristic type II azole binding spectra were obtained with AF51B, whereas an additional trough and a blue-shifted spectral peak were present in AF51A binding spectra for all azoles except clotrimazole. This suggests two distinct azole binding conformations within the heme prosthetic group of AF51A. All five azoles bound relatively weakly to AF51A, with K(d) values ranging from 1 μM for itraconazole to 11.9 μM for fluconazole. The azole binding properties of purified AF51A and AF51B suggest an explanation for the intrinsic azole (fluconazole) resistance observed in Aspergillus fumigatus.
|
DRUGMATRIX: CYP450, 3A4 enzyme inhibition (substrate: 7-Benzyloxy-4-(trifluoromethyl)-coumarin)
|
None
|
900.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Fungistatic activity against Saccharomyces cerevisiae ATCC 24657 assessed as cell proliferation at 90.7 uM after 24 hrs by agar plate bioassay relative to control
|
Saccharomyces cerevisiae
|
95.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Antifungal activities of novel non-azole molecules against S. cerevisiae and C. albicans.
Year : 2012
Volume : 47
First Page : 270
Last Page : 277
Authors : Tani N, Rahnasto-Rilla M, Wittekindt C, Salminen KA, Ritvanen A, Ollakka R, Koskiranta J, Raunio H, Juvonen RO.
Abstract : Because of the increasing number of immunocompromised patients and due to problems with antifungal treatment, especially with the most widely used antifungals, azoles, there is an urgent need for new, potent and safe antifungals with fewer cytochrome P450 (CYP)-mediated interactions with other drugs. In the present study, 54 novel non-azole molecules were selected with the help of molecular modelling and virtual molecule database screening to identify new fungistatic or fungicidic compounds with functional groups that would produce reactive intermediates killing the yeast cells. Database screening and selection of tested compounds were based on the construction of two pharmacophores and docking hits to the active site of the CYP51 homology model. Inhibition potency of the compounds was tested against Saccharomyces cerevisiae and/or Candida albicans. Two new structured compounds, 2-({4-[(2-cyanoethyl)(methyl) amino]benzylidene} amino)-5-(3,4-dimethoxyphenyl)-4-methylthiophene-3-carbonitrile and 2-[([1,1'-biphenyl]-4-ylmethylene)amino]-5-(3,4-dimethoxyphenyl)-4-methylthiophene-3-carbonitrile were discovered to have promising antifungal properties based on bioassays. Inhibition screen of human hepatic CYP enzymes revealed that these two compounds did not inhibit potently five human recombinant CYP enzymes. The results of this study indicate that the functional groups of the two compounds may produce reactive intermediates when located at the active site of CYP51.
|
TP_TRANSPORTER: inhibition of Calcein-AM efflux in Mdr1a-expressing LLC-PK1 cells
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
TP_TRANSPORTER: inhibition of Calcein-AM efflux in Mdr1b-expressing LLC-PK1 cells
|
None
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
22.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-2.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
59.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inverse agonist activity at CCR4 in human HTLA cells assessed as depression of basal activity incubated for 20 mins by beta arrestin-recruitment mediated luciferase reporter gene assay in absence of CCL22
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Colloidal aggregation causes inhibition of G protein-coupled receptors.
Year : 2013
Volume : 56
Issue : 6
First Page : 2406
Last Page : 2414
Authors : Sassano MF, Doak AK, Roth BL, Shoichet BK.
Abstract : Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field.
|
Inhibition of vasopressin-stimulated vasopressin V2 receptor in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay
|
Homo sapiens
|
800.0
nM
|
|
Inhibition of vasopressin-stimulated vasopressin V2 receptor in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Colloidal aggregation causes inhibition of G protein-coupled receptors.
Year : 2013
Volume : 56
Issue : 6
First Page : 2406
Last Page : 2414
Authors : Sassano MF, Doak AK, Roth BL, Shoichet BK.
Abstract : Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field.
|
Inhibition of CX3CL1-stimulated CX3CR1 in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay
|
Homo sapiens
|
100.0
nM
|
|
Inhibition of CX3CL1-stimulated CX3CR1 in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay
|
Homo sapiens
|
158.49
nM
|
|
Journal : J. Med. Chem.
Title : Colloidal aggregation causes inhibition of G protein-coupled receptors.
Year : 2013
Volume : 56
Issue : 6
First Page : 2406
Last Page : 2414
Authors : Sassano MF, Doak AK, Roth BL, Shoichet BK.
Abstract : Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field.
|
Inhibition of CCL22-stimulated CCR4 in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay
|
Homo sapiens
|
500.0
nM
|
|
Inhibition of CCL22-stimulated CCR4 in human HTLA cells pre-incubated for 20 mins measured on day 4 by beta arrestin-recruitment mediated luciferase reporter gene assay
|
Homo sapiens
|
501.19
nM
|
|
Journal : J. Med. Chem.
Title : Colloidal aggregation causes inhibition of G protein-coupled receptors.
Year : 2013
Volume : 56
Issue : 6
First Page : 2406
Last Page : 2414
Authors : Sassano MF, Doak AK, Roth BL, Shoichet BK.
Abstract : Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field.
|
Cytotoxicity against african green monkey Vero cells after 48 hrs by MTT assay
|
Chlorocebus sabaeus
|
50.0
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and antifungal activity of terpenyl-1,4-naphthoquinone and 1,4-anthracenedione derivatives.
Year : 2013
Volume : 67
First Page : 19
Last Page : 27
Authors : Castro MÁ, Gamito AM, Tangarife-Castaño V, Zapata B, Miguel del Corral JM, Mesa-Arango AC, Betancur-Galvis L, San Feliciano A.
Abstract : The antifungal evaluation of twenty seven simple and heterocycle-fused prenyl-1,4-naphthoquinones and 1,4-anthracenediones was performed in vitro against human pathogenic yeasts (Candida spp.) and filamentous fungi (Aspergillus spp., Fusarium spp., and Trichophyton spp.). The synthetic strategy used to obtain the quinone derivatives was initially based on the Diels-Alder cycloaddition between myrcene and several p-benzoquinone derivatives, followed by cyclisation of the prenyl side chain in the case of anthracene-1,4-diones. The most promising compounds, displaying MIC values in the low μg/mL range, were those bearing one or two chlorine atoms attached to the quinone ring. Time-kill curves determined for the most potent compounds showed their fungistatic mode of action similar to that of itraconazole.
|
Cytotoxicity against human A549 cells after 48 hrs by MTT assay
|
Homo sapiens
|
182.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-Candidal activity of N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide.
Year : 2014
Volume : 24
Issue : 5
First Page : 1299
Last Page : 1302
Authors : Bhat MA, Khan AA, Khan S, Al-Omar MA, Parvez MK, Al-Dosari MS, Al-Dhfyan A.
Abstract : Eighteen N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide derivatives were synthesized, evaluated against ten clinical isolates of Candida spp. and compared with itraconazole. Introduction of p-chloro (2c), p-iodo (2q), m-chloro (2l) and o-nitro (2r) substitution at phenyl ring of thiosemicarbazide enhanced the anti-Candida activity. Compound (2c) bearing p-cholorophenyl ring was found to be the most effective against Candida albicans ATCC 66027, Candida spp. 12810 (blood) and Candida spp. 178 (HVS) with MIC value of 0.09-0.78 μg/mL, whereas itraconazole exhibits the inhibitory activity with MIC value of 0.04-1.56 μg/mL against all tested strains. There is a correlation between anti-Candidal activity and p-chloro substitution at phenyl ring of thiosemicarbazide. All synthesized compounds were investigated for their potential cytotoxicity against non cancer cell line MCF-10A. The active compounds 2c, 2r and 2a were further investigated for their cytotoxic effects on three cancer cell lines; HT1080 (skin), HepG2 (liver) and A549 (lung). The active compounds showed minimal cytotoxic activity against non cancer cell line and all three cancer cell lines. Moreover, compound 2c displaying better activity against C. albicans ATCC66027 and Candida spp. [blood] compared to reference drug (itraconazole), represents a good lead for the development of newer, potent and broad spectrum anti-Candidal agents.
|
Cytotoxicity against human HT1080 cells after 48 hrs by MTT assay
|
Homo sapiens
|
201.63
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-Candidal activity of N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide.
Year : 2014
Volume : 24
Issue : 5
First Page : 1299
Last Page : 1302
Authors : Bhat MA, Khan AA, Khan S, Al-Omar MA, Parvez MK, Al-Dosari MS, Al-Dhfyan A.
Abstract : Eighteen N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide derivatives were synthesized, evaluated against ten clinical isolates of Candida spp. and compared with itraconazole. Introduction of p-chloro (2c), p-iodo (2q), m-chloro (2l) and o-nitro (2r) substitution at phenyl ring of thiosemicarbazide enhanced the anti-Candida activity. Compound (2c) bearing p-cholorophenyl ring was found to be the most effective against Candida albicans ATCC 66027, Candida spp. 12810 (blood) and Candida spp. 178 (HVS) with MIC value of 0.09-0.78 μg/mL, whereas itraconazole exhibits the inhibitory activity with MIC value of 0.04-1.56 μg/mL against all tested strains. There is a correlation between anti-Candidal activity and p-chloro substitution at phenyl ring of thiosemicarbazide. All synthesized compounds were investigated for their potential cytotoxicity against non cancer cell line MCF-10A. The active compounds 2c, 2r and 2a were further investigated for their cytotoxic effects on three cancer cell lines; HT1080 (skin), HepG2 (liver) and A549 (lung). The active compounds showed minimal cytotoxic activity against non cancer cell line and all three cancer cell lines. Moreover, compound 2c displaying better activity against C. albicans ATCC66027 and Candida spp. [blood] compared to reference drug (itraconazole), represents a good lead for the development of newer, potent and broad spectrum anti-Candidal agents.
|
Cytotoxicity against human HepG2 cells after 48 hrs by MTT assay
|
Homo sapiens
|
142.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and anti-Candidal activity of N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide.
Year : 2014
Volume : 24
Issue : 5
First Page : 1299
Last Page : 1302
Authors : Bhat MA, Khan AA, Khan S, Al-Omar MA, Parvez MK, Al-Dosari MS, Al-Dhfyan A.
Abstract : Eighteen N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide derivatives were synthesized, evaluated against ten clinical isolates of Candida spp. and compared with itraconazole. Introduction of p-chloro (2c), p-iodo (2q), m-chloro (2l) and o-nitro (2r) substitution at phenyl ring of thiosemicarbazide enhanced the anti-Candida activity. Compound (2c) bearing p-cholorophenyl ring was found to be the most effective against Candida albicans ATCC 66027, Candida spp. 12810 (blood) and Candida spp. 178 (HVS) with MIC value of 0.09-0.78 μg/mL, whereas itraconazole exhibits the inhibitory activity with MIC value of 0.04-1.56 μg/mL against all tested strains. There is a correlation between anti-Candidal activity and p-chloro substitution at phenyl ring of thiosemicarbazide. All synthesized compounds were investigated for their potential cytotoxicity against non cancer cell line MCF-10A. The active compounds 2c, 2r and 2a were further investigated for their cytotoxic effects on three cancer cell lines; HT1080 (skin), HepG2 (liver) and A549 (lung). The active compounds showed minimal cytotoxic activity against non cancer cell line and all three cancer cell lines. Moreover, compound 2c displaying better activity against C. albicans ATCC66027 and Candida spp. [blood] compared to reference drug (itraconazole), represents a good lead for the development of newer, potent and broad spectrum anti-Candidal agents.
|
Antiproliferative activity against mouse medulloblastoma cells expressing wild type SMO
|
Mus musculus
|
55.0
nM
|
|
Journal : MedChemComm
Title : Hedgehog signalling pathway inhibitors as cancer suppressing agents
Year : 2014
Volume : 5
Issue : 2
First Page : 117
Last Page : 133
Authors : Trinh TN, McLaughlin EA, Gordon CP, McCluskey A
|
Inhibition of CYP3A4 in human hepatocytes using testosterone as substrate by HPLC/MS/MS method
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and optimization of highly-selective fungal CYP51 inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3455
Last Page : 3458
Authors : Hoekstra WJ, Garvey EP, Moore WR, Rafferty SW, Yates CM, Schotzinger RJ.
Abstract : While the orally-active azoles such as voriconazole and itraconazole are effective antifungal agents, they potently inhibit a broad range of off-target human cytochrome P450 enzymes (CYPs) leading to various safety issues (e.g., drug-drug interactions, liver toxicity). Herein, we describe rationally-designed, broad-spectrum antifungal agents that are more selective for the target fungal enzyme, CYP51, than related human CYP enzymes such as CYP3A4. Using proprietary methodology, the triazole metal-binding group found in current clinical agents was replaced with novel, less avid metal-binding groups in concert with potency-enhancing molecular scaffold modifications. This process produced a unique series of fungal CYP51-selective inhibitors that included the oral antifungal 7d (VT-1161), now in Phase 2 clinical trials. This series exhibits excellent potency against key yeast and dermatophyte strains. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases.
|
DNDI: Chagas in Vitro, 96 hour
|
Trypanosoma cruzi
|
4.0
nM
|
|
Title : Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning
Authors : Kaiser M, Mäser P, Tadoori LP, Ioset JR, Brun R.
Abstract : In this study, a set of 100 registered drugs with drug repositioning potential for neglected tropical diseases was assembled. The compound collection was systematically screened against protozoan parasites, namely T. b. rhodesiense, L. donovani, T. cruzi and P. falciparum. Several drugs and drug classes exhibited in vitro activity and selectivity against one of the protozoan parasites. The results offer opportunities for drug repurposing and the identified compound classes could also be a starting point for new drug discovery projects. See also publication: Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015 10(8): e0135556.
|
Inhibition of CYP3A4.1 (unknown origin)-mediated testosterone 6beta-hydroxylation incubated for 10 mins prior to NADPH addition measured after 20 mins by HPLC-UV analysis
|
Homo sapiens
|
76.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.
Year : 2011
Volume : 39
Issue : 4
First Page : 724
Last Page : 728
Authors : Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H.
Abstract : CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.
|
Inhibition of CYP3A4.2 (unknown origin)-mediated testosterone 6beta-hydroxylation incubated for 10 mins prior to NADPH addition measured after 20 mins by HPLC-UV analysis
|
Homo sapiens
|
45.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.
Year : 2011
Volume : 39
Issue : 4
First Page : 724
Last Page : 728
Authors : Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H.
Abstract : CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.
|
Inhibition of CYP3A4.7 (unknown origin)-mediated testosterone 6beta-hydroxylation incubated for 10 mins prior to NADPH addition measured after 20 mins by HPLC-UV analysis
|
Homo sapiens
|
179.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.
Year : 2011
Volume : 39
Issue : 4
First Page : 724
Last Page : 728
Authors : Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H.
Abstract : CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.
|
Inhibition of CYP3A4.16 (unknown origin)-mediated testosterone 6beta-hydroxylation incubated for 10 mins prior to NADPH addition measured after 20 mins by HPLC-UV analysis
|
Homo sapiens
|
41.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.
Year : 2011
Volume : 39
Issue : 4
First Page : 724
Last Page : 728
Authors : Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H.
Abstract : CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.
|
Inhibition of CYP3A4.18 (unknown origin)-mediated testosterone 6beta-hydroxylation incubated for 10 mins prior to NADPH addition measured after 20 mins by HPLC-UV analysis
|
Homo sapiens
|
82.0
nM
|
|
Journal : Drug Metab. Dispos.
Title : Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.
Year : 2011
Volume : 39
Issue : 4
First Page : 724
Last Page : 728
Authors : Akiyoshi T, Saito T, Murase S, Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H.
Abstract : CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the K(i) values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.
|
Inhibition of hedgehog pathway in mouse C3H10T1/2 cells assessed as downregulation of Gli1 mRNA expression after 24 hrs by qPCR method
|
Mus musculus
|
63.0
nM
|
|
Journal : J. Med. Chem.
Title : Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
Year : 2016
Volume : 59
Issue : 8
First Page : 3635
Last Page : 3649
Authors : Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ, Hadden MK.
Abstract : Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
|
Inhibition of hedgehog pathway in mouse ASZ cells assessed as downregulation of Gli1 mRNA expression after 48 hrs by qPCR method
|
Mus musculus
|
140.0
nM
|
|
Journal : J. Med. Chem.
Title : Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
Year : 2016
Volume : 59
Issue : 8
First Page : 3635
Last Page : 3649
Authors : Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ, Hadden MK.
Abstract : Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
|
Inhibition of CYP3A4 in human liver microsomes using testosterone as substrate after 10 mins by LC/MS/MS analysis
|
Homo sapiens
|
50.4
nM
|
|
Journal : J. Med. Chem.
Title : Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
Year : 2016
Volume : 59
Issue : 8
First Page : 3635
Last Page : 3649
Authors : Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ, Hadden MK.
Abstract : Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
|
Inhibition of hedgehog pathway in mouse MERP MB cells assessed as downregulation of Gli1 mRNA expression after 48 hrs by qPCR method
|
Mus musculus
|
390.0
nM
|
|
Journal : J. Med. Chem.
Title : Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
Year : 2016
Volume : 59
Issue : 8
First Page : 3635
Last Page : 3649
Authors : Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ, Hadden MK.
Abstract : Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
|
Inhibition of hedgehog pathway in mouse Shh-Light2 cells after 46 hrs by luciferase reporter gene assay
|
Mus musculus
|
690.0
nM
|
|
Journal : J. Med. Chem.
Title : Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
Year : 2016
Volume : 59
Issue : 8
First Page : 3635
Last Page : 3649
Authors : Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ, Hadden MK.
Abstract : Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
|
Antiproliferative activity against HUVEC assessed as inhibition of VEGF induced cell proliferation using methyl-[3H]thymidine after 36 hrs
|
Homo sapiens
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic.
Year : 2016
Volume : 59
Issue : 8
First Page : 3635
Last Page : 3649
Authors : Pace JR, DeBerardinis AM, Sail V, Tacheva-Grigorova SK, Chan KA, Tran R, Raccuia DS, Wechsler-Reya RJ, Hadden MK.
Abstract : Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogues for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochemically defined des-triazole ITZ analogues also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
|
Inhibition of Orai1-mediated store operated Ca2+ entry in human MDA-MB-231 cells assessed as reduction of SERCA inhibition-induced ER release at 100 uM preincubated for 15 mins followed by CPA addition by PBX-based FLIPR assay
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg Med Chem
Title : Evaluation of known and novel inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a Fluorescence Imaging Plate Reader assay.
Year : 2017
Volume : 25
Issue : 1
First Page : 440
Last Page : 449
Authors : Azimi I, Flanagan JU, Stevenson RJ, Inserra M, Vetter I, Monteith GR, Denny WA.
Abstract : The Orai1 Ca2+ permeable ion channel is an important component of store operated Ca2+ entry (SOCE) in cells. It's over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure-activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains.
|
Inhibition of Orai1-mediated store operated Ca2+ entry in human MDA-MB-231 cells assessed as reduction in BAPTA-induced Ca2+ depletion-stimulated SOCE activity at 100 uM preincubated for 15 mins followed by BAPTA addition in presence of extracellular Ca2+ by PBX-based FLIPR assay relative to control
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg Med Chem
Title : Evaluation of known and novel inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a Fluorescence Imaging Plate Reader assay.
Year : 2017
Volume : 25
Issue : 1
First Page : 440
Last Page : 449
Authors : Azimi I, Flanagan JU, Stevenson RJ, Inserra M, Vetter I, Monteith GR, Denny WA.
Abstract : The Orai1 Ca2+ permeable ion channel is an important component of store operated Ca2+ entry (SOCE) in cells. It's over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays. The assay was also used in a screening project seeking novel inhibitors. Following a broad literature survey of classes of calcium channel inhibitors we used simplified ligand structures to query the ZINC on-line database, and following two iterations of refinement selected a novel Orai1-selective dichlorophenyltriazole hit compound. Analogues of this were synthesized and evaluated in the FLIPR assay to develop structure-activity relationships (SAR) for the three domains of the hit; triazole (head), dichlorophenyl (body) and substituted phenyl (tail). For this series, the results suggested the need for a lipophilic tail domain and an out-of-plane twist between the body and tail domains.
|
Inhibition of CYP3A4 in human liver microsomes assessed as reduction in nifedipine oxidation incubated for 10 mins
|
Homo sapiens
|
32.6
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies.
Year : 2017
Volume : 25
Issue : 2
First Page : 750
Last Page : 758
Authors : Zhao D, Zhao S, Zhao L, Zhang X, Wei P, Liu C, Hao C, Sun B, Su X, Cheng M.
Abstract : Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125-2μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization.
|
Antileishmanial activity against wild type Leishmania major LV39 Rho/SU/59/P promastigote forms after 48 hrs
|
Leishmania major
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview of azoles targeting sterol 14α-demethylase for antileishmanial therapy.
Year : 2017
Volume : 135
First Page : 241
Last Page : 259
Authors : Emami S, Tavangar P, Keighobadi M.
Abstract : The azole antifungal drugs are an important class of chemotherapeutic agents with broad-spectrum of activity against yeasts and filamentous fungi, act in the ergosterol biosynthetic pathway through inhibition of the cytochrome P450-dependent enzyme sterol 14α-demethylase. Azole antifungals have also been repurposed for treatment of tropical protozoan infections including human leishmaniasis. Recent advances in molecular biology and computational chemistry areas have increased our knowledge about sterol biochemical pathway in Leishmania parasites. Based on the importance of sterol biosynthetic pathway in Leishmania parasites, we reviewed all studies reported on azoles for potential antileishmanial therapy along their structural and biological aspects. This review may help medicinal chemists for design of new azole-derived antileishmanial drugs.
|
Antileishmanial activity against Leishmania major LV39 Rho/SU/59/P promastigote forms harboring c14dm-/+C14DM mutant after 48 hrs
|
Leishmania major
|
400.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview of azoles targeting sterol 14α-demethylase for antileishmanial therapy.
Year : 2017
Volume : 135
First Page : 241
Last Page : 259
Authors : Emami S, Tavangar P, Keighobadi M.
Abstract : The azole antifungal drugs are an important class of chemotherapeutic agents with broad-spectrum of activity against yeasts and filamentous fungi, act in the ergosterol biosynthetic pathway through inhibition of the cytochrome P450-dependent enzyme sterol 14α-demethylase. Azole antifungals have also been repurposed for treatment of tropical protozoan infections including human leishmaniasis. Recent advances in molecular biology and computational chemistry areas have increased our knowledge about sterol biochemical pathway in Leishmania parasites. Based on the importance of sterol biosynthetic pathway in Leishmania parasites, we reviewed all studies reported on azoles for potential antileishmanial therapy along their structural and biological aspects. This review may help medicinal chemists for design of new azole-derived antileishmanial drugs.
|
Anti-angiogenic activity against HUVEC after 24 hrs by scintillation counting based [3H]-thymidine incorporation assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : J Med Chem
Title : Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition.
Year : 2018
Volume : 61
Issue : 24
First Page : 11158
Last Page : 11168
Authors : Li Y, Pasunooti KK, Li RJ, Liu W, Head SA, Shi WQ, Liu JO.
Abstract : Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.
|
Inhibition of human liver microsome CYP3A4 at 1 uM expressed in baculosomes using fluorogenic-DBOMF as substrate preincubated for 10 mins followed by substrate addition and measured after 60 mins by fluorescence based assay
|
Homo sapiens
|
84.0
%
|
|
Journal : J Med Chem
Title : Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition.
Year : 2018
Volume : 61
Issue : 24
First Page : 11158
Last Page : 11168
Authors : Li Y, Pasunooti KK, Li RJ, Liu W, Head SA, Shi WQ, Liu JO.
Abstract : Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.
|
Antiangiogenic activity in HUVEC assessed as inhibition of tube formation at 5 uM after 24 hrs by matrigel assay relative to control
|
Homo sapiens
|
45.0
%
|
|
Journal : J Med Chem
Title : Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 Inhibition.
Year : 2018
Volume : 61
Issue : 24
First Page : 11158
Last Page : 11168
Authors : Li Y, Pasunooti KK, Li RJ, Liu W, Head SA, Shi WQ, Liu JO.
Abstract : Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clinical studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivatives in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogues, 15n with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, 15n induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that 15n is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.
|
Inhibition of Smo-mediated hedgehog signaling pathway in mouse Light2 cells in Shh conditioned medium after 48 hrs by Gli-Renilla luciferase reporter gene assay
|
Mus musculus
|
690.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Current trends in Hedgehog signaling pathway inhibition by small molecules.
Year : 2018
Volume : 28
Issue : 19
First Page : 3131
Last Page : 3140
Authors : Ghirga F, Mori M, Infante P.
Abstract : The Hedgehog (Hh) signaling pathway is a widely appreciated target for anticancer therapy. However, drug resistance at the Smoothened receptor (SMO) and Hh activation downstream/independently of SMO seriously limit the clinical use of SMO antagonists. Here, we address the main strategies that have been recently established to inhibit the Hh pathway and to bypass the above limitations. Particularly, we review efforts that have been spent to develop novel and potent SMO antagonists able to modulate the drug-resistant forms of SMO, to discover efficient glioma-associated oncogene (GLI) antagonists and inhibitors of GLI-mediated transcription, and to establish and assay promising combination of multiple agents with enhanced Hh inhibition at lower individual doses.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-4.93
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of Hedgehog signaling pathway in mouse ASZ001 cells assessed as decrease in Gli1 mRNA expression after 48 hrs by qRT-PCR analysis
|
Mus musculus
|
140.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Truncated Itraconazole Analogues Exhibiting Potent Anti-Hedgehog Activity and Improved Drug-like Properties.
Year : 2019
Volume : 10
Issue : 9
First Page : 1290
Last Page : 1295
Authors : Wen J, Chennamadhavuni D, Morel SR, Hadden MK.
Abstract : We conducted a structure-activity relationship study to explore simplified analogues of the itraconazole (ITZ) scaffold for their ability to inhibit the hedgehog (Hh) signaling pathway. These analogues were based on exploring the effects of chemical modifications to the linker and triazolone/side chain region of ITZ. Analogue <b>11</b> was identified as the most potent compound in our first generation, with an IC<sub>50</sub> value of 81 nM in a murine Hh-dependent basal cell carcinoma. Metabolic identification studies led us to identify truncated piperazine (<b>26</b>) as the major metabolite in human liver microsomes (HLMs) and an improved Hh pathway inhibitor (IC<sub>50</sub> = 22 nM). This work verifies that continued truncation of the ITZ scaffold is a practical method to maintain potent anti-Hh activity while also reducing the molecular weight for the ITZ scaffold and achieving improved pharmacokinetic properties.
|
Inhibition of mouse Smo A1 mutant expressed in mouse Shh Light2 cells assessed as reduction in hedgehog pathway activation incubated for 30 hrs by luminescence assay
|
Mus musculus
|
800.0
nM
|
|
Journal : J Med Chem
Title : Inhibiting Hedgehog: An Update on Pharmacological Compounds and Targeting Strategies.
Year : 2019
Volume : 62
Issue : 18
First Page : 8392
Last Page : 8411
Authors : Galperin I, Dempwolff L, Diederich WE, Lauth M.
Abstract : Important steps in embryonic development are governed by the Hedgehog (Hh) signaling pathway, an evolutionary conserved signal transduction cascade. However, Hh activity not only is crucial during embryo formation but also is involved in adult tissue repair and in several malignancies. Particularly due to its link to cancer, small molecule Hh pathway inhibitors have been developed and the first compounds have been approved for use in Hh-driven basal cell carcinoma. Almost all advanced Hh inhibitors target the critical signaling component Smoothened (SMO), but preclinical research has identified additional compounds that can block the Hh pathway along its entire signaling cascade, which, in light of emerging drug resistance occurring with SMO inhibitors, is of high importance. Herein we give an overview on currently known Hh pathway inhibitors, delineating their respective strengths and weaknesses and describing potential drug targeting strategies to interfere with Hh signaling in different cancer settings.
|
Inhibition of CYP3A4 in human liver microsomes by LC-MS/MS analysis
|
Homo sapiens
|
40.0
nM
|
|
Journal : Eur J Med Chem
Title : Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors.
Year : 2019
Volume : 163
First Page : 320
Last Page : 332
Authors : Teske KA, Dash RC, Morel SR, Chau LQ, Wechsler-Reya RJ, Hadden MK.
Abstract : Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that π-π interactions between the compound and Smoothened play a key role in stabilizing the bound analogues.
|
Inhibition of human ERG expressed in CHO cells at 25 uM by electrophysiology assay relative to control
|
Homo sapiens
|
1.0
%
|
|
Journal : Eur J Med Chem
Title : Development of posaconazole-based analogues as hedgehog signaling pathway inhibitors.
Year : 2019
Volume : 163
First Page : 320
Last Page : 332
Authors : Teske KA, Dash RC, Morel SR, Chau LQ, Wechsler-Reya RJ, Hadden MK.
Abstract : Inhibition of the hedgehog (Hh) signaling pathway has been validated as a therapeutic strategy to treat basal cell carcinoma and holds potential for several other forms of human cancer. Itraconazole and posaconazole are clinically useful triazole anti-fungals that are being repurposed as anti-cancer agents based on their ability to inhibit the Hh pathway. We have previously demonstrated that removal of the triazole from itraconazole does not affect its ability to inhibit the Hh pathway while abolishing its primary side effect, potent inhibition of Cyp3A4. To develop structure-activity relationships for the related posaconazole scaffold, we synthesized and evaluated a series of des-triazole analogues designed through both ligand- and structure-based methods. These compounds demonstrated improved anti-Hh properties compared to posaconazole and enhanced stability without inhibiting Cyp3A4. In addition, we utilized a series of molecular dynamics and binding energy studies to probe specific interactions between the compounds and their proposed binding site on Smoothened. These studies strongly suggest that the tetrahydrofuran region of the scaffold projects out of the binding site and that π-π interactions between the compound and Smoothened play a key role in stabilizing the bound analogues.
|
Inhibition of human ERG
|
Homo sapiens
|
1.0
%
|
|
Journal : J Med Chem
Title : Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors.
Year : 2019
Volume : 62
Issue : 8
First Page : 3873
Last Page : 3885
Authors : Pace JR, Teske KA, Chau LQ, Dash RC, Zaino AM, Wechsler-Reya RJ, Hadden MK.
Abstract : The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.
|
Inhibition of CYP3A4 (unknown origin) using midazolam as substrate by UPLC-MS/MS analysis
|
Homo sapiens
|
0.04
%
|
|
Journal : J Med Chem
Title : Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors.
Year : 2019
Volume : 62
Issue : 8
First Page : 3873
Last Page : 3885
Authors : Pace JR, Teske KA, Chau LQ, Dash RC, Zaino AM, Wechsler-Reya RJ, Hadden MK.
Abstract : The Food and Drug Administration-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionalities (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.
|
Antifungal activity against Histoplasma capsulatum G217B after 10 to 14 days by microscopic method
|
Histoplasma capsulatum
|
0.001
ug.mL-1
|
|
Journal : J Nat Prod
Title : Secondary Metabolites of Onygenales Fungi Exemplified by Aioliomyces pyridodomos.
Year : 2019
Volume : 82
Issue : 6
First Page : 1616
Last Page : 1626
Authors : Lin Z, Kakule TB, Reilly CA, Beyhan S, Schmidt EW.
Abstract : Fungi from the order Onygenales include human pathogens. Although secondary metabolites are critical for pathogenic interactions, relatively little is known about Onygenales compounds. Here, we use chemical and genetic methods on Aioliomyces pyridodomos, the first representative of a candidate new family within Onygenales. We isolated 14 new bioactive metabolites, nine of which are first disclosed here. Thirty-two specialized metabolite biosynthetic gene clusters (BGCs) were identified. BGCs were correlated to some of the new compounds by heterologous expression of biosynthetic genes. Some of the compounds were found after one year of fermentation. By comparing BGCs from A. pyridodomos with those from 68 previously sequenced Onygenales fungi, we delineate a large biosynthetic potential. Most of these biosynthetic pathways are specific to Onygenales fungi and have not been found elsewhere. Family level specificity and conservation of biosynthetic gene content are evident within Onygenales. Identification of these compounds may be important to understanding pathogenic interactions.
|
Antileishmanial activity against Leishmania amazonensis MHOM/BR/75/Josefa promastigotes assessed as reduction in parasite viability after 72 hrs by Neubauer chamber counting method
|
Leishmania amazonensis
|
440.0
nM
|
|
Journal : Eur J Med Chem
Title : Multi-target drugs active against leishmaniasis: A paradigm of drug repurposing.
Year : 2019
Volume : 183
First Page : 111660
Last Page : 111660
Authors : Braga SS.
Abstract : This mini-review focuses on leishmanicidal drugs that were sourced from small molecules previously approved for other diseases. The mechanisms of action of these molecules are herein explored, to probe the origins of their inter-species growth inhibitory activities. It is shown how the transversal action of the azoles - fluconazole, posaconazole and itraconazole - in both fungi and Leishmania is due to the occurrence of the same target, lanosterol 14-α-demethylase, in these two groups of species. In turn, the drugs miltefosine and amphotericin B are presented as truly multi-target agents, acting on small molecules, proteins, genes and even organelles. Steps towards future leishmanicidal drug candidates based on the multi-target strategy and on drug repurposing are also briefly presented.
|
Antileishmanial activity against Leishmania amazonensis MHOM/BR/75/Josefa intracellular amastigotes infected in CF-1 macrophages assessed as reduction in parasite viability after 72 hrs by optical microscopic method
|
Leishmania amazonensis
|
80.0
nM
|
|
Journal : Eur J Med Chem
Title : Multi-target drugs active against leishmaniasis: A paradigm of drug repurposing.
Year : 2019
Volume : 183
First Page : 111660
Last Page : 111660
Authors : Braga SS.
Abstract : This mini-review focuses on leishmanicidal drugs that were sourced from small molecules previously approved for other diseases. The mechanisms of action of these molecules are herein explored, to probe the origins of their inter-species growth inhibitory activities. It is shown how the transversal action of the azoles - fluconazole, posaconazole and itraconazole - in both fungi and Leishmania is due to the occurrence of the same target, lanosterol 14-α-demethylase, in these two groups of species. In turn, the drugs miltefosine and amphotericin B are presented as truly multi-target agents, acting on small molecules, proteins, genes and even organelles. Steps towards future leishmanicidal drug candidates based on the multi-target strategy and on drug repurposing are also briefly presented.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.23
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
2.535
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.12
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
8.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
8.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.12
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
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Inhibition of Hedgehog signaling pathway in mouse ASZ001 cells assessed as decrease in Gli1 mRNA expression after 48 hrs by qRT-PCR analysis
|
Mus musculus
|
140.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Inhibition of hedgehog signaling by stereochemically defined des-triazole itraconazole analogues.
Year : 2020
Volume : 30
Issue : 2
First Page : 126794
Last Page : 126794
Authors : Wen J, Teske KA, Kyle Hadden M.
Abstract : Dysregulation of the hedgehog (Hh) signaling pathway is associated with cancer occurrence and development in various malignancies. Previous structure-activity relationships (SAR) studies have provided potent Itraconazole (ITZ) analogues as Hh pathway antagonists. To further expand on our SAR for the ITZ scaffold, we synthesized and evaluated a series of compounds focused on replacing the triazole. Our results demonstrate that the triazole region is amenable to modification to a variety of different moieties; with a single methyl group representing the most favorable substituent. In addition, nonpolar substituents were more active than polar substituents. These SAR results provide valuable insight into the continued exploration of ITZ analogues as Hh pathway antagonists.
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Inhibition of NPC1/VDAC1 in HUVEC cells assessed as reduction in cell proliferation pretreated for 24 hrs followed by [3H]thymidine incorporation by scintillation counter method
|
Homo sapiens
|
170.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Design and Synthesis of Tetrazole- and Pyridine-Containing Itraconazole Analogs as Potent Angiogenesis Inhibitors.
Year : 2020
Volume : 11
Issue : 6
First Page : 1111
Last Page : 1117
Authors : Li Y, Pasunooti KK, Peng H, Li RJ, Shi WQ, Liu W, Cheng Z, Head SA, Liu JO.
Abstract : Itraconazole, a widely used antifungal drug, was found to possess antiangiogenic activity and is currently undergoing multiple clinical trials for the treatment of different types of cancer. However, it suffers from extremely low solubility and strong interactions with many drugs through inhibition of CYP3A4, limiting its potential as a new antiangiogenic and anticancer drug. To address these issues, a series of analogs in which the phenyl group is replaced with pyridine or fluorine-substituted benzene was synthesized. Among them the pyridine- and tetrazole-containing compound <b>24</b> has significantly improved solubility and reduced CYP3A4 inhibition compared to itraconazole. Similar to itraconazole, compound <b>24</b> inhibited the AMPK/mTOR signaling axis and the glycosylation of VEGFR2. It also induced cholesterol accumulation in the endolysosome and demonstrated binding to the sterol-sensing domain of NPC1 in a simulation study. These results suggested that compound <b>24</b> may serve as an attractive candidate for the development of a new generation of antiangiogenic drug.
|
Inhibition of CYP3A4 in human liver microsome using Nifedipine as a substrate incubated for 10 mins in the presence of NADPH by LC-MS/MS analysis
|
Homo sapiens
|
32.6
nM
|
|
