|
Inhibitory effect on human recombinant liver cytochrome P450 2C9 expressed in yeast strain
|
None
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of sulfaphenazole derivatives and their use as inhibitors and tools for comparing the active sites of human liver cytochromes P450 of the 2C subfamily.
Year : 2001
Volume : 44
Issue : 22
First Page : 3622
Last Page : 3631
Authors : Ha-Duong NT, Dijols S, Marques-Soares C, Minoletti C, Dansette PM, Mansuy D.
Abstract : Twenty-three new derivatives of sulfaphenazole (SPA) were synthesized to further explore the topology of the active sites of human liver cytochromes P450 of the 2C subfamily and to find new selective inhibitors of these cytochromes. These compounds are derived from SPA by replacement of the NH(2) and H (of the SO(2)NH function) substituents of SPA with various R(1) and R(2) groups, respectively. Their inhibitory effects were studied on recombinant CYP 2C8, 2C9, 2C18, and 2C19 expressed in yeast. High affinities for CYP 2C9 (IC(50) < 1 microM) were only observed for SPA derivatives having the SO(2)NH function and a relatively small R(1) substituent (R(1) = NH(2), CH(3)). Any increase in the size of R(1) led to a moderate decrease of the affinity, and the N-alkylation of the SO(2)NH function of SPA to a greater decrease of this affinity. The same structural changes led to opposite effects on molecular recognition by CYP 2C8 and 2C18, which generally exhibited similar behaviors. Thus, contrary to CYP 2C9, CYP 2C8 and 2C18 generally prefer neutral compounds with relatively large R(1) and R(2) substituents. CYP 2C19 showed an even lower affinity for anionic compounds than CYP 2C8 and 2C18. However, as CYP 2C8 and 2C18, CYP 2C19 showed a much better affinity for neutral compounds derived from N-alkylation of SPA and for anionic compounds bearing a larger R(1) substituent. One of the new compounds (R(1) = methyl, R(2) = propyl) inhibited all human CYP 2Cs with IC(50) values between 10 and 20 microM, while another one (R(1) = allyl, R(2) = methyl) inhibited all CYP 2Cs except CYP 2C9, and a third one (R(1) = R(2) = methyl) inhibited all CYP 2Cs except CYP 2C8. Only 2 compounds of the 25 tested derivatives were highly selective toward one human CYP 2C; these are SPA and compound 1 (R(1) = CH(3), R(2) = H), which acted as selective CYP 2C9 inhibitors. However, some SPA derivatives selectively inhibited CYP 2C8 and 2C18. Since CYP 2C18 is hardly detectable in human liver, these derivatives could be interesting molecules to selectively inhibit CYP 2C8 in human liver microsomes. Thus, compound 11 (R(1) = NH(2), R(2) = (CH(2))(2)CH(CH(3))(2)) appears to be particularly interesting for that purpose as its IC(50) value for CYP 2C8 is low (3 microM) and 20-fold smaller than those found for CYP 2C9 and 2C19.
|
Binding affinity measured on human cytochrome P450 2C9 (CYP2C9) enzyme
|
None
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : A refined 3-dimensional QSAR of cytochrome P450 2C9: computational predictions of drug interactions.
Year : 2000
Volume : 43
Issue : 15
First Page : 2789
Last Page : 2796
Authors : Rao S, Aoyama R, Schrag M, Trager WF, Rettie A, Jones JP.
Abstract : A ligand-based model is reported that predicts the Ki values for cytochrome P450 2C9 (CYP2C9) inhibitors. This CoMFA model was used to predict the affinity of 14 structurally diverse compounds not in the training set and appears to be robust. The mean error of the predictions is 6 microM. The experimentally measured Ki values of the 14 compounds range from 0.1 to 48 microM. Leave-one-out cross-validated partial least-squares gives a q2 value of between 0.6 and 0.8 for the various models which indicates internal consistency. Random assignment of biological data to structure leads to negative q2 values. These models are useful in that they establish a pharmacophore for binding to CYP2C9 that can be tested with site-directed mutagenesis. These models can also be used to screen for potential drug interactions and to design compounds that will not bind to this enzyme with high affinity.
|
Binding affinity towards cytochrome P450 2C9
|
None
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors.
Year : 2004
Volume : 47
Issue : 4
First Page : 907
Last Page : 914
Authors : Afzelius L, Zamora I, Masimirembwa CM, Karlén A, Andersson TB, Mecucci S, Baroni M, Cruciani G.
Abstract : A conformer- and alignment-independent three-dimensional structure-activity relationship (3D-QSAR) model has been derived that is based on flexible molecular interaction fields calculated in GRID and the subsequent description of these fields by use of alignment-independent descriptors derived in ALMOND. The training set consisted of 22 diverse and flexible competitive inhibitors of the drug-metabolizing enzyme CYP2C9 and generated a model with r(2) of 0.81 and q(2) of 0.62. The predicitive capacity of the model was externally evaluated with a test set of 12 competitive inhibitors and 11 out of 12 were predicted within 0.5 log unit. The most relevant points of interaction in the model correlated well to the amino acids involved in CYP2C9-substrate/inhibitor binding in the active site of a CYP2C9 homology model, further validating the mechanistic sense of our model. This approach offers the possibility to derive predicitve 3D-QSAR models without the need for an alignment rule for chemically diverse ligands and in the absence of target protein crystal structure information.
|
Inhibition of CYP2C9 in human liver microsomes
|
Homo sapiens
|
350.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist.
Year : 2007
Volume : 50
Issue : 4
First Page : 807
Last Page : 819
Authors : Liverton NJ, Bednar RA, Bednar B, Butcher JW, Claiborne CF, Claremon DA, Cunningham M, DiLella AG, Gaul SL, Libby BE, Lyle EA, Lynch JJ, McCauley JA, Mosser SD, Nguyen KT, Stump GL, Sun H, Wang H, Yergey J, Koblan KS.
Abstract : The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
|
Inhibition of human CYP2C9
|
Homo sapiens
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluation of (hydroxyphenyl)naphthalene and -quinoline derivatives: potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) for the treatment of estrogen-dependent diseases.
Year : 2008
Volume : 51
Issue : 7
First Page : 2158
Last Page : 2169
Authors : Frotscher M, Ziegler E, Marchais-Oberwinkler S, Kruchten P, Neugebauer A, Fetzer L, Scherer C, Müller-Vieira U, Messinger J, Thole H, Hartmann RW.
Abstract : Human 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent estradiol (E2). This reaction takes place in the target cell where the estrogenic effect is exerted via the estrogen receptor (ER). Estrogens, especially E2, are known to stimulate the proliferation of hormone-dependent diseases. 17beta-HSD1 is overexpressed in many breast tumors. Thus, it is an attractive target for the treatment of these diseases. Ligand- and structure-based drug design led to the discovery of novel, selective, and potent inhibitors of 17beta-HSD1. Phenyl-substituted bicyclic moieties were synthesized as mimics of the steroidal substrate. Computational methods were used to obtain insight into their interactions with the protein. Compound 5 turned out to be a highly potent inhibitor of 17beta-HSD1 showing good selectivity (17beta-HSD2, ERalpha and beta), medium cell permeation, reasonable metabolic stability (rat hepatic microsomes), and little inhibition of hepatic CYP enzymes.
|
Inhibition of human recombinant CYP2C9 expressed in insect microsomes
|
Homo sapiens
|
318.0
nM
|
|
Journal : J. Med. Chem.
Title : Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity.
Year : 2008
Volume : 51
Issue : 16
First Page : 5064
Last Page : 5074
Authors : Heim R, Lucas S, Grombein CM, Ries C, Schewe KE, Negri M, Müller-Vieira U, Birk B, Hartmann RW.
Abstract : Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect. With respect to CYP11B2 inhibition, some substituents induced a dramatic increase in inhibitory potency. The methoxyalkyl derivatives 22 and 26 are the most potent CYP11B2 inhibitors up to now (IC50 = 0.2 nM). Most compounds also clearly discriminated between CYP11B2 and CYP11B1, and the CYP1A2 potency significantly decreased in some cases (e.g., isoquinoline derivative 30 displayed only 6% CYP1A2 inhibition at 2 microM concentration). Furthermore, isoquinoline derivative 28 proved to be capable of passing the gastrointestinal tract and reached the general circulation after peroral administration to male Wistar rats.
|
Inhibition of human recombinant CYP2C9 expressed in baculovirus-infected insect microsomes
|
Homo sapiens
|
318.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach.
Year : 2008
Volume : 51
Issue : 19
First Page : 6138
Last Page : 6149
Authors : Lucas S, Heim R, Negri M, Antes I, Ries C, Schewe KE, Bisi A, Gobbi S, Hartmann RW.
Abstract : Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.
|
Inhibition of human CYP2C9
|
Homo sapiens
|
250.0
nM
|
|
Journal : J. Med. Chem.
Title : New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases.
Year : 2011
Volume : 54
Issue : 2
First Page : 534
Last Page : 547
Authors : Marchais-Oberwinkler S, Wetzel M, Ziegler E, Kruchten P, Werth R, Henn C, Hartmann RW, Frotscher M.
Abstract : Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17β-estradiol in patients with estrogen-dependent diseases like breast cancer or endometriosis. With the aim of optimizing the biological profile of 17β-HSD1 inhibitors from the hydroxyphenylnaphthol class, structural optimizations were performed at the 1-position of the naphthalene by introduction of different heteroaromatic rings as well as substituted phenyl groups. In the latter class of compounds, which were synthesized applying Suzuki-cross coupling, the 3-methanesulfonamide 15 turned out to be a highly potent 17β-HSD1 inhibitor (IC(50) = 15 nM in a cell-free assay). It was also very active in the cellular assay (T47D cells, IC(50) = 71 nM) and selective toward 17β-HSD2 and the estrogen receptors α and β. It showed a good membrane permeation and metabolic stability and was orally available in the rat.
|
Inhibition of human CYP2C9 expressed in baculovirus-infected insect microsomes
|
Homo sapiens
|
318.0
nM
|
|
Journal : J. Med. Chem.
Title : Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives.
Year : 2011
Volume : 54
Issue : 7
First Page : 2307
Last Page : 2319
Authors : Lucas S, Negri M, Heim R, Zimmer C, Hartmann RW.
Abstract : Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis. Among these, ethyl-substituted 3 possesses high selectivity against CYP1A2. Rigidification of 3 by incorporation of the ethyl group into a 5- or 6-membered ring affords compounds with a pyrroloquinolinone or pyridoquinolinone molecular scaffold (e.g., 4 and 5). It was found that these molecules are even more potent and selective CYP11B2 inhibitors than their corresponding open-chain analogues. Moreover, pyrroloquinolinone 4 exhibits no inhibition of the six most important hepatic CYP enzymes as well as a bioavailability in the range of the marketed drug fadrozole. The SAR studies disclose that subtle changes in the heterocyclic moiety are responsible for either a strong or a weak inhibition of the highly homologous 11β-hydroxylase (CYP11B1). These results are not only important for fine-tuning the selectivity of CYP11B2 inhibitors but also for the development of selective CYP11B1 inhibitors that are of interest for the treatment of Cushing's syndrome and metabolic syndrome.
|
DRUGMATRIX: CYP450, 2C9 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
200.0
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
|
Inhibition of CYP2C9 at 5 uM by fluorsecence-based assay
|
None
|
69.0
%
|
|
Journal : J. Med. Chem.
Title : Virtual screening targeting the urokinase receptor, biochemical and cell-based studies, synthesis, pharmacokinetic characterization, and effect on breast tumor metastasis.
Year : 2011
Volume : 54
Issue : 20
First Page : 7193
Last Page : 7205
Authors : Wang F, Li J, Sinn AL, Knabe WE, Khanna M, Jo I, Silver JM, Oh K, Li L, Sandusky GE, Sledge GW, Nakshatri H, Jones DR, Pollok KE, Meroueh SO.
Abstract : Virtual screening targeting the urokinase receptor (uPAR) led to (±)-3-(benzo[d][1,3]dioxol-5-yl)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-phenylbutan-1-amine 1 (IPR-1) and N-(3,5-dimethylphenyl)-1-(4-isopropylphenyl)-5-(piperidin-4-yl)-1H-pyrazole-4-carboxamide 3 (IPR-69). Synthesis of an analogue of 1, namely, 2 (IPR-9), and 3 led to breast MDA-MB-231 invasion, migration and adhesion assays with IC(50) near 30 μM. Both compounds blocked angiogenesis with IC(50) of 3 μM. Compounds 2 and 3 inhibited cell growth with IC(50) of 6 and 18 μM and induced apoptosis. Biochemical assays revealed leadlike properties for 3, but not 2. Compound 3 administered orally reached peak concentration of nearly 40 μM with a half-life of about 2 h. In NOD-SCID mice inoculated with breast TMD-231 cells in their mammary fat pads, compound 3 showed a 20% reduction in tumor volumes and less extensive metastasis was observed for the treated mice. The suitable pharmacokinetic properties of 3 and the encouraging preliminary results in metastasis make it an ideal starting point for next generation compounds.
|
Inhibition of CYP2C9 at 10 uM
|
None
|
90.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of novel potent HCV NS5A inhibitors.
Year : 2012
Volume : 22
Issue : 14
First Page : 4864
Last Page : 4868
Authors : Zhang H, Zhou L, Amblard F, Shi J, Bobeck DR, Tao S, McBrayer TR, Tharnish PM, Whitaker T, Coats SJ, Schinazi RF.
Abstract : Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented.
|
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
|
16.9
%
|
|
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
|
0.7
%
|
|
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
|
17.1
%
|
|
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 CYP2C9 at 10 uM
|
Homo sapiens
|
90.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of non-dimeric HCV NS5A inhibitors.
Year : 2013
Volume : 23
Issue : 7
First Page : 2031
Last Page : 2034
Authors : Amblard F, Zhang H, Zhou L, Shi J, Bobeck DR, Nettles JH, Chavre S, McBrayer TR, Tharnish P, Whitaker T, Coats SJ, Schinazi RF.
Abstract : Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).
|
Inhibition of CYP2C9 in human liver microsomes using (S)-warfarin as substrate after 30 mins
|
Homo sapiens
|
67.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Semisynthesis, cytotoxicity, antiviral activity, and drug interaction liability of 7-O-methylated analogues of flavonolignans from milk thistle.
Year : 2013
Volume : 21
Issue : 13
First Page : 3919
Last Page : 3926
Authors : Althagafy HS, Graf TN, Sy-Cordero AA, Gufford BT, Paine MF, Wagoner J, Polyak SJ, Croatt MP, Oberlies NH.
Abstract : Silymarin, an extract of the seeds of milk thistle (Silybum marianum), is used as an herbal remedy, particularly for hepatoprotection. The main chemical constituents in silymarin are seven flavonolignans. Recent studies explored the non-selective methylation of one flavonolignan, silybin B, and then tested those analogues for cytotoxicity and inhibition of both cytochrome P450 (CYP) 2C9 activity in human liver microsomes and hepatitis C virus infection in a human hepatoma (Huh7.5.1) cell line. In general, enhanced bioactivity was observed with the analogues. To further probe the biological consequences of methylation of the seven major flavonolignans, a series of 7-O-methylflavonolignans were generated. Optimization of the reaction conditions permitted selective methylation at the phenol in the 7-position in the presence of each metabolite's 4-5 other phenolic and/or alcoholic positions without the use of protecting groups. These 7-O-methylated analogues, in parallel with the corresponding parent compounds, were evaluated for cytotoxicity against Huh7.5.1 cells; in all cases the monomethylated analogues were more cytotoxic than the parent compounds. Moreover, parent compounds that were relatively non-toxic and inactive or weak inhibitors of hepatitis C virus infection had enhanced cytotoxicity and anti-HCV activity upon 7-O-methylation. Also, the compounds were tested for inhibition of major drug metabolizing enzymes (CYP2C9, CYP3A4/5, UDP-glucuronsyltransferases) in pooled human liver or intestinal microsomes. Methylation of flavonolignans differentially modified inhibitory potency, with compounds demonstrating both increased and decreased potency depending upon the compound tested and the enzyme system investigated. In total, these data indicated that monomethylation modulates the cytotoxic, antiviral, and drug interaction potential of silymarin flavonolignans.
|
Inhibition of CYP3A4 in human liver microsomes assessed as midazolam hydroxylation to 1'-hydroxymidazolam at 10 uM after 10 mins relative to control
|
Homo sapiens
|
21.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP2D6 in human liver microsomes assessed as bufuralol hydroxylation to 4'-hydroxybufuralol at 10 uM after 10 mins relative to control
|
Homo sapiens
|
7.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP1A2 in human liver microsomes assessed as phenacetin demethylation to acetaminophen at 10 uM after 10 mins relative to control
|
Homo sapiens
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of CYP2C9 in human liver microsomes assessed as tolbutamide hydroxylation to hydroxytolbutamide at 10 uM after 10 mins relative to control
|
Homo sapiens
|
92.0
%
|
|
Journal : J. Med. Chem.
Title : Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents.
Year : 2013
Volume : 56
Issue : 19
First Page : 7651
Last Page : 7668
Authors : Choi JY, Calvet CM, Gunatilleke SS, Ruiz C, Cameron MD, McKerrow JH, Podust LM, Roush WR.
Abstract : A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (KD ≤ 42 nM; EC50 = 0.65 μM), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 μM). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
104.55
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
98.59
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of CYP2C9 (unknown origin) at 10 uM relative to control
|
Homo sapiens
|
75.79
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Potent Hepatitis C Virus NS5A Inhibitors Containing a Benzidine Core.
Year : 2014
Volume : 5
Issue : 3
First Page : 255
Last Page : 258
Authors : Bae IH, Choi JK, Chough C, Keum SJ, Kim H, Jang SK, Kim BM.
Abstract : Here we report the discovery of a series of potent hepatitis C virus (HCV) NS5A inhibitors based on the benzidine prolinamide backbone. Taking a simple synthetic route, we developed a novel inhibitor structure, which allows easy modification, and through optimization of the capping group, we identified compound 6 with highly potent anti-HCV activity. Compound 6 is nontoxic and is anticipated to be an effective HCV drug candidate.
|
Inhibition of recombinant CYP2C9 (unknown origin) using 7-methoxy-4-trifluoromethylcoumarin as substrate
|
Homo sapiens
|
180.0
nM
|
|
Journal : J. Med. Chem.
Title : Investigation of a novel series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones as human immunodeficiency virus type 1 integrase inhibitors.
Year : 2014
Volume : 57
Issue : 11
First Page : 4640
Last Page : 4660
Authors : Suchaud V, Bailly F, Lion C, Calmels C, Andréola ML, Christ F, Debyser Z, Cotelle P.
Abstract : We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range associated with low micromolar anti-HIV activities were obtained. We investigated the influence of substitution at position 7 on biological activity. Introduction of electron-withdrawing functional groups such as the nitro moiety at position 7 led to a noticeable improvement of antiviral activity, down to low nanomolar anti-HIV potencies, with advantageous therapeutic indexes going close to those of the clinically used raltegravir and retained potencies against a panel of IN mutants.
|
Inhibition of human CYP2C9 at 10 uM
|
Homo sapiens
|
96.0
%
|
|
Journal : J. Med. Chem.
Title : Development of (E)-2-((1,4-dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: Novel 2-amidinophenylbenzamides as potent inhibitors of venezuelan equine encephalitis virus.
Year : 2014
Volume : 57
Issue : 20
First Page : 8608
Last Page : 8621
Authors : Schroeder CE, Yao T, Sotsky J, Smith RA, Roy S, Chu YK, Guo H, Tower NA, Noah JW, McKellip S, Sosa M, Rasmussen L, Smith LH, White EL, Aubé J, Jonsson CB, Chung D, Golden JE.
Abstract : Venezuelan equine encephalitis virus (VEEV) is an emerging pathogenic alphavirus that can cause significant disease in humans. Given the absence of therapeutic options available and the significance of VEEV as a weaponized agent, an optimization effort was initiated around a quinazolinone screening hit 1 with promising cellular antiviral activity (EC50 = 0.8 μM), limited cytotoxic liability (CC50 > 50 μM), and modest in vitro efficacy in reducing viral progeny (63-fold at 5 μM). Scaffold optimization revealed a novel rearrangement affording amidines, specifically compound 45, which was found to potently inhibit several VEEV strains in the low nanomolar range without cytotoxicity (EC50 = 0.02-0.04 μM, CC50 > 50 μM) while limiting in vitro viral replication (EC90 = 0.17 μM). Brain exposure was observed in mice with 45. Significant protection was observed in VEEV-infected mice at 5 mg kg(-1) day(-1) and viral replication appeared to be inhibited through interference of viral nonstructural proteins.
|
Inhibition of recombinant human CYP2C9 preincubated at 10 uM for 5 mins before fluorescent substrate addition by fluorescence assay
|
Homo sapiens
|
11.3
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3234
Last Page : 3237
Authors : Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG.
Abstract : We report the synthesis of 3-phenethylazetidine derivatives 2 and their biological activities against 5-HT, NE and DA transporters as well as microsomal stability, CYP inhibition, and hERG inhibition profiles. Compound 2at showed most potent triple reuptake inhibitor with good selectivity as a candidate for depression.
|
Inhibition of CYP2C9 in human liver microsome
|
Homo sapiens
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists.
Year : 2014
Volume : 24
Issue : 17
First Page : 4271
Last Page : 4275
Authors : Park EJ, Ahn YG, Jung SH, Bang HJ, Kim M, Hong DJ, Kim J, Suh KH, Kim YJ, Kim D, Kim EY, Lee K, Min KH.
Abstract : Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.
|
Inhibitory activity of 3 uM sulfaphenazole on 56 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
83.0
%
|
|
Title : FDA drug approval package for Aliskiren hemifumarate
Abstract : Drug Approval Package documents downloaded from Drugs@FDA. Data extracted from various pdfs.
- hERG study and start of ADME section: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf
- ADME/PK studies, metabolic schemes: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P2.pdf
- Marmoset toxicity study including PK parameters: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P3.pdf
- Metabolism studies and human PK: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf
- human metabolic scheme: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf
- human metabolic scheme: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P3.pdf
|
Inhibitory activity of 3 uM sulfaphenazole on 59 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
82.0
%
|
|
Title : FDA drug approval package for Aliskiren hemifumarate
Abstract : Drug Approval Package documents downloaded from Drugs@FDA. Data extracted from various pdfs.
- hERG study and start of ADME section: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf
- ADME/PK studies, metabolic schemes: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P2.pdf
- Marmoset toxicity study including PK parameters: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P3.pdf
- Metabolism studies and human PK: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf
- human metabolic scheme: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf
- human metabolic scheme: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P3.pdf
|
Inhibitory activity of 3 uM sulfaphenazole on 80 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
75.0
%
|
|
Title : FDA drug approval package for Aliskiren hemifumarate
Abstract : Drug Approval Package documents downloaded from Drugs@FDA. Data extracted from various pdfs.
- hERG study and start of ADME section: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P1.pdf
- ADME/PK studies, metabolic schemes: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P2.pdf
- Marmoset toxicity study including PK parameters: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_PharmR_P3.pdf
- Metabolism studies and human PK: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P1.pdf
- human metabolic scheme: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P2.pdf
- human metabolic scheme: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_ClinPharmR_P3.pdf
|
Inhibition of human CYP2C9 at 10 uM preincubated for 10 mins with cofactor followed by mixture of enzyme-substrate addition by fluorescence assay relative to control
|
Homo sapiens
|
93.7
%
|
|
Journal : MedChemComm
Title : Osthol and curcumin as inhibitors of human Pgp and multidrug efflux pumps of Staphylococcus aureus: reversing the resistance against frontline antibacterial drugs
Year : 2014
Volume : 5
Issue : 10
First Page : 1540
Last Page : 1547
Authors : Joshi P, Singh S, Wani A, Sharma S, Jain SK, Singh B, Gupta BD, Satti NK, Koul S, Khan IA, Kumar A, Bharate SB, Vishwakarma RA
|
Inhibition of CYP2C9 (unknown origin) using luciferin tagged substrate preincubated for 10 mins before substrate addition
|
Homo sapiens
|
80.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of potent and selective cytotoxic activity of new quinazoline-ureas against TMZ-resistant glioblastoma multiforme (GBM).
Year : 2015
Volume : 103
First Page : 210
Last Page : 222
Authors : Elkamhawy A, Viswanath AN, Pae AN, Kim HY, Heo JC, Park WK, Lee CO, Yang H, Kim KH, Nam DH, Seol HJ, Cho H, Roh EJ.
Abstract : Herein, we report new quinazoline-urea based compounds with potent cytotoxic activities against TMZ-resistant glioblastoma multiforme (GBM) cells. Low micromolar IC₅₀ values were exhibited over a panel of three primary GBM patient-derived cell cultures belonging to proneural (GBM-1), mesenchymal (GBM-2), and classical (GBM-3) subtypes. Eight compounds showed excellent selectivity indices for GBM cells comparing to a normal astrocyte cell line. In JC-1 assay, analogues 11, 12, 20, 22, and 24 exerted promising rates of mPTP opening induction towards proneural GBM subtype. Compounds 11, 20, and 24 bound to the translocator protein 18 kDa (TSPO) in submicromolar range using [(3)H] PK-11195 binding affinity assay. A homology model was built and docked models of 11, 12, 20, 22 and 24 were generated for describing their plausible binding modes in TSPO. In 3D clonogenic assay, compound 20 manifested potent tumoricidal effects on TMZ-resistant GBM cells even at submicromolar concentrations. In addition, CYP450 and hERG assays presented a safe toxicity profile of 20. Taken as a whole, this report presents compound 20 as a potent, selective and safe GBM cytotoxic agent which constitutes a promising direction against TMZ-resistant GBM.
|
Inhibition of human recombinant CYP2C9 using MFC as substrate incubated for 40 mins by fluorimetry
|
Homo sapiens
|
180.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs) as human immunodeficiency virus type 1 integrase inhibitors: Influence of the alkylcarboxamide substitution of position 4.
Year : 2016
Volume : 117
First Page : 256
Last Page : 268
Authors : Billamboz M, Suchaud V, Bailly F, Lion C, Andréola ML, Christ F, Debyser Z, Cotelle P.
Abstract : Herein, we report further insight into the biological activities displayed by the 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) scaffold. Previous studies have evidenced the marked fruitful effect of substitution of this two-metal binding pharmacophore at position 4 by phenyl and benzyl carboxamido chains. Strong human immunodeficiency virus type 1 integrase (HIV-1 IN) inhibitors in the low nanomolar range with micromolar (even down to low nanomolar) anti-HIV activities were obtained. Keeping this essential 4-carboxamido function, we investigated the influence of the replacement of phenyl and benzyl groups by various alkyl chains. This study shows that the recurrent halogenobenzyl pharmacophore found in the INSTIs can be efficiently replaced by an n-alkyl group. With an optimal length of six carbons, we observed a biological profile and a high barrier to resistance equivalent to those of a previously reported hit compound bearing a 4-fluorobenzyl group.
|
Inhibition of CYP2C9 in human liver microsomes using tolbutamide as substrate after 20 mins by LC-MS analysis
|
Homo sapiens
|
740.0
nM
|
|
Journal : J. Med. Chem.
Title : Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism.
Year : 2016
Volume : 59
Issue : 7
First Page : 3340
Last Page : 3352
Authors : Carosati E, Cosimelli B, Ioan P, Severi E, Katneni K, Chiu FC, Saponara S, Fusi F, Frosini M, Matucci R, Micucci M, Chiarini A, Spinelli D, Budriesi R.
Abstract : We present a series of oxadiazolothiazinones, selective inotropic agents on isolated cardiac tissues, devoid of chronotropy and vasorelaxant activity. Functional and binding data for the precursor of the series (compound 1) let us hypothesize LTCC blocking activity and the existence of a recognition site specific for this scaffold. We synthesized and tested 22 new derivatives: introducing a para-methoxyphenyl at C-8 led to compound 12 (EC50 = 0.022 μM), twice as potent as its para-bromo analogue (1). For 10 analogues, we extended the characterization of the biological properties by including the assessment of metabolic stability in human liver microsomes and cytochrome P450 inhibition potential. We observed that the methoxy group led to active compounds with low metabolic stability and high CYP inhibition, whereas the protective effect of bromine resulted in enhanced metabolic stability and reduced CYP inhibition. Thus, we identified two para-bromo benzothiazino-analogues as candidates for further studies.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate at 10 uM preincubated for 5 mins followed by NADPH addition measured after 10 mins by LC-MS/MS analysis relative to control
|
Homo sapiens
|
98.0
%
|
|
Journal : J. Med. Chem.
Title : Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker.
Year : 2016
Volume : 59
Issue : 10
First Page : 4913
Last Page : 4925
Authors : Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB.
Abstract : Neuronal nitric oxide synthase (nNOS) is an important therapeutic target for the treatment of various neurodegenerative disorders. A major challenge in the design of nNOS inhibitors focuses on potency in humans and selectivity over other NOS isoforms. Here we report potent and selective human nNOS inhibitors based on the 2-aminopyridine scaffold with a central pyridine linker. Compound 14j, the most promising inhibitor in this study, exhibits excellent potency for rat nNOS (Ki = 16 nM) with 828-fold n/e and 118-fold n/i selectivity with a Ki value of 13 nM against human nNOS with 1761-fold human n/e selectivity. Compound 14j also displayed good metabolic stability in human liver microsomes, low plasma protein binding, and minimal binding to cytochromes P450 (CYPs), although it had little to no Caco-2 permeability.
|
Inhibition of CYP2C9 in human liver using microsomes diclofenac as substrate preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC/MS/MS method
|
Homo sapiens
|
704.0
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.
|
Fluorescent High Throughput P450 Assay: The interaction of SC12 with cytochrome P450 enzymes was tested using Fluorescent High Throughput P450 assays (Gentest); The IC50s of the compounds was calculated on isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5). Inhibition of the P450 isoforms was measured in specific assays using specific substrates that become fluorescent upon CYP metabolism. Compounds, dissolved in ACN (acetonitrile) (CYP2E1, CYP2C8, CYP2B6, CYP3A5) or DMSO (all remaining isoforms), were tested in duplicate (n=2) in concentration-response curves (eight concentrations) in a 96-well plate containing incubation/NADPH regenerating buffer. Specific isoenzymes and substrates were added and incubated at 37° C. Reactions were terminated at different times, depending on the assays, and plates read on a Fluoroskan Ascent at the appropriate emission/excitation wavelengths. Concentration-response curves performed in duplicate for known inhibitors for each isoenzyme were tested in ever
|
Homo sapiens
|
270.0
nM
|
|
Title : Phospholipid drug analogs
Year : 2015
|
Fluorescent High Throughput P450 Assays: The interaction of SC12 with cytochrome P450 enzymes was tested using Fluorescent High Throughput P450 assays (Gentest); The IC50s of the compounds was calculated on isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2D6, CYP2E1, CYP3A4 and CYP3A5).Materials and Methods: Inhibition of the P450 isoforms was measured in specific assays using specific substrates that become fluorescent upon CYP metabolism. Compounds, dissolved in ACN (acetonitrile) (CYP2E1, CYP2C8, CYP2B6, CYP3A5) or DMSO (all remaining isoforms), were tested in duplicate (n=2) in concentration-response curves (eight concentrations) in a 96-well plate containing incubation/NADPH regenerating buffer. Specific isoenzymes and substrates were added and incubated at 37° C. Reactions were terminated at different times, depending on the assays, and plates read on a Fluoroskan Ascent at the appropriate emission/excitation wavelengths.
|
Homo sapiens
|
270.0
nM
|
|
Title : Phospholipid drug analogs
Year : 2015
|
Inhibition of CYP2C9 in human liver microsomes using tolbutamide as substrate after 5 to 15 mins
|
Homo sapiens
|
205.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin.
Year : 2017
Volume : 8
Issue : 3
First Page : 321
Last Page : 326
Authors : Metcalf B, Chuang C, Dufu K, Patel MP, Silva-Garcia A, Johnson C, Lu Q, Partridge JR, Patskovska L, Patskovsky Y, Almo SC, Jacobson MP, Hua L, Xu Q, Gwaltney SL, Yee C, Harris J, Morgan BP, James J, Xu D, Hutchaleelaha A, Paulvannan K, Oksenberg D, Li Z.
Abstract : We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC/MS/MS analysis
|
Homo sapiens
|
535.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents.
Year : 2017
Volume : 137
First Page : 96
Last Page : 107
Authors : Zhao S, Zhang X, Wei P, Su X, Zhao L, Wu M, Hao C, Liu C, Zhao D, Cheng M.
Abstract : To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compounds (1), a series of aromatic heterocyclic derivatives were designed, synthesized and evaluated for in vitro antifungal activity. Many of the target compounds showed good inhibitory activity against Candida albicans and Cryptococcus neoformans. In particular, the isoxazole nuclei were more suited for improving the activity against Aspergillus spp. Among these compounds, 2-F substituted analogues 23g and 23h displayed the most remarkable in vitro activity against Candida spp., C. neoformans, A. fumigatus and fluconazole-resistant C.alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and voriconazole. Notably, the compounds 23g and 23h exhibited low inhibition profiles for various isoforms of human cytochrome P450 and excellent blood plasma stability.
|
Inhibition of CYP2C9 in human liver microsomes assessed as tolbutamide methylhydroxylation after 4 to 40 mins in presence of NADPH by LCMS analysis
|
Homo sapiens
|
720.0
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria.
Year : 2018
Volume : 26
Issue : 11
First Page : 2996
Last Page : 3005
Authors : O' Neill PM, Stocks PA, Sabbani S, Roberts NL, Amewu RK, Shore ER, Aljayyoussi G, Angulo-Barturén I, Belén M, Jiménez-Díaz, Bazaga SF, Martínez MS, Campo B, Sharma R, Charman SA, Ryan E, Chen G, Shackleford DM, Davies J, Nixon GL, Biagini GA, Ward SA.
Abstract : A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate preincubated for 10 mins followed by NADPH addition measured after 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
462.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and evaluation of benzoheterocycle analogues as potent antifungal agents targeting CYP51.
Year : 2018
Volume : 26
Issue : 12
First Page : 3242
Last Page : 3253
Authors : Zhao S, Wei P, Wu M, Zhang X, Zhao L, Jiang X, Hao C, Su X, Zhao D, Cheng M.
Abstract : To further enhance the anti-Aspergillus efficacy of our previously discovered antifungal lead compound 1, a series of benzoheterocycle analogues were designed, synthesized and evaluated for their in vitro antifungal activity. The most promising compounds 13s and 14a exhibited excellent antifungal activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. albicans strains, that was superior or comparable to those of the reference drugs fluconazole and voriconazole. GC-MS analyses suggested that the novel compound 13s might have a similar mechanism to fluconazole by inhibiting fungal lanosterol 14α-demethylase (CYP51). Furthermore, compounds 13s and 14a exhibited low inhibition profiles for various human cytochrome P450 isoforms as well as excellent blood plasma stability.
|
Inhibition of CYP2C9 in human liver microsomes at 5 uM using diclofenac sodium as substrate by LC-MS/MS analysis relative to control
|
Homo sapiens
|
94.9
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of a series of novel GPR40 agonists containing nitrogen heterocyclic rings.
Year : 2018
Volume : 28
Issue : 18
First Page : 3050
Last Page : 3056
Authors : Sun Z, Zhou T, Pan X, Yang Y, Huan Y, Xiao Z, Shen Z, Liu Z.
Abstract : A novel series of GPR40 agonists is designed by introducing nitrogen-containing heterocyclic ring at the terminal phenyl ring of TAK-875 with the aim of decreasing its lipophilicity. Three different β-substituted phenylpropionic acids were investigated as the acidic components. A total of 34 compounds have been synthesized, among which, compound 30 exhibited comparable GPR40 agonistic activity in vitro with TAK-875 and relatively lower lipophilicity through calculation (30, EC50 = 1.2 μM, cLogP = 1.3; TAK-875: EC50 = 5.1 μM, cLogP = 3.4). Moreover, compound 30 was able to enhance the insulin secretion of primary islets isolated from normal ICR mice and showed no obvious inhibition against cytochromes P450 in vitro. In vivo, compound 30 exhibited efficacy in oral glucose tolerance test (oGTT) in normal ICR mice.
|
Inhibition of recombinant human CYP2C9 expressed in insect cell microsomes at 10 uM using Luciferin-H as substrate preincubated for 30 mins followed by NADPH addition measured after 30 mins by luminometric method
|
Homo sapiens
|
98.0
%
|
|
Journal : Eur J Med Chem
Title : Hedgehog pathway inhibitors of the acylthiourea and acylguanidine class show antitumor activity on colon cancer in vitro and in vivo.
Year : 2018
Volume : 157
First Page : 368
Last Page : 379
Authors : Vesci L, Milazzo FM, Stasi MA, Pace S, Manera F, Tallarico C, Cini E, Petricci E, Manetti F, De Santis R, Giannini G.
Abstract : Small series of acylguanidine and acylthiourea derivatives were synthesized in gram-scale and assayed for their ability to modulate the Hh signalling pathway. In vitro studies showed a low micromolar inhibitory activity toward tumor cell lines, while the oral administration revealed an excellent ADME profile in vivo. Compound 5 emerged as the most active and safe inhibitor of colon cancer cells both in vitro and in a xenograft mouse model. Based on these data, 5 could be prioritized to further development with the perspective of clinical studies.
|
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
|
-3.33
%
|
|
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 CYP2C9 in pooled human liver microsomes pre-incubated for 5 mins before NADPH addition and measured after 10 mins by UPLC-MS/MS analysis relative to control
|
Homo sapiens
|
685.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.
Year : 2019
Volume : 62
Issue : 23
First Page : 10563
Last Page : 10582
Authors : Ramdas V, Talwar R, Banerjee M, Joshi AA, Das AK, Walke DS, Borhade P, Dhayagude U, Loriya R, Gote G, Bommakanti A, Sivaram A, Agarwal G, Goswami A, Nigade P, Mehta M, Patil V, Modi D, Kumar H, Mallurwar S, Dash A, Modi F, Kuldharan S, Srivastava P, Singh M, Narasimham L, Gundu J, Sharma S, Kamboj RK, Palle VP.
Abstract : The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac substrate incubated for 10 mins in presence of NADPH
|
Homo sapiens
|
660.0
nM
|
|
Journal : J Med Chem
Title : Structure-Based Bioisosterism Yields HIV-1 NNRTIs with Improved Drug-Resistance Profiles and Favorable Pharmacokinetic Properties.
Year : 2020
Volume : 63
Issue : 9
First Page : 4837
Last Page : 4848
Authors : Kang D, Feng D, Sun Y, Fang Z, Wei F, De Clercq E, Pannecouque C, Liu X, Zhan P.
Abstract : The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate after 10 mins in presence of NADPH
|
Homo sapiens
|
660.0
nM
|
|
Journal : J Med Chem
Title : Identification of Dihydrofuro[3,4- d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties.
Year : 2019
Volume : 62
Issue : 3
First Page : 1484
Last Page : 1501
Authors : Kang D, Zhang H, Wang Z, Zhao T, Ginex T, Luque FJ, Yang Y, Wu G, Feng D, Wei F, Zhang J, De Clercq E, Pannecouque C, Chen CH, Lee KH, Murugan NA, Steitz TA, Zhan P, Liu X.
Abstract : To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4- d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC<sub>50</sub> = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.
|
Inhibition of human CYP2C9 in human liver microsomes at 50 times IC50 concentration relative to control
|
Homo sapiens
|
96.5
%
|
|
Journal : J Med Chem
Title : Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors.
Year : 2019
Volume : 62
Issue : 3
First Page : 1138
Last Page : 1166
Authors : Vögerl K, Ong N, Senger J, Herp D, Schmidtkunz K, Marek M, Müller M, Bartel K, Shaik TB, Porter NJ, Robaa D, Christianson DW, Romier C, Sippl W, Jung M, Bracher F.
Abstract : The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate after 10 mins in presence of NADP by LC-MS/MS analysis
|
Homo sapiens
|
847.0
nM
|
|
Journal : J Med Chem
Title : Exploiting the Tolerant Region I of the Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Binding Pocket: Discovery of Potent Diarylpyrimidine-Typed HIV-1 NNRTIs against Wild-Type and E138K Mutant Virus with Significantly Improved Water Solubility and Favorable Safety Profiles.
Year : 2019
Volume : 62
Issue : 4
First Page : 2083
Last Page : 2098
Authors : Huang B, Chen W, Zhao T, Li Z, Jiang X, Ginex T, Vílchez D, Luque FJ, Kang D, Gao P, Zhang J, Tian Y, Daelemans D, De Clercq E, Pannecouque C, Zhan P, Liu X.
Abstract : Diarylpyrimidine derivatives (DAPYs) exhibit robust anti-HIV-1 potency, although they have been compromised by E138K variant and severe side-effects and been suffering from poor water solubility. In the present work, hydrophilic morpholine or methylsulfonyl and sulfamide-substituted piperazine/piperidines were introduced into the right wing of DAPYs targeting the solvent-exposed tolerant region I. The anti-HIV-1 activities of 11c (EC50(WT) = 0.0035 μM, EC50(E138K) = 0.0075 μM) were the same as and 2-fold better than that of the lead etravirine against the wild-type and E138K mutant HIV-1, respectively, with a relative low cytotoxicity (CC50 ≥ 173 μM). Further test showed a significant improvement in the water solubility of 11c. Besides, 11c displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute/subacute toxicities at doses of 2000 mg·kg-1/50 mg·kg-1 in mice. Taken together, we consider that 11c is a promising lead for further structural optimization.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac substrate in presence of NADPH incubated for 10 mins
|
Homo sapiens
|
609.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel.
Year : 2020
Volume : 63
Issue : 3
First Page : 1298
Last Page : 1312
Authors : Kang D, Ruiz FX, Feng D, Pilch A, Zhao T, Wei F, Wang Z, Sun Y, Fang Z, De Clercq E, Pannecouque C, Arnold E, Liu X, Zhan P.
Abstract : Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.
|
Inhibition of human CYP2C9 by fluorescence method
|
Homo sapiens
|
280.0
nM
|
|
Journal : J Med Chem
Title : Development of Robust 17(R),18(S)-Epoxyeicosatetraenoic Acid (17,18-EEQ) Analogues as Potential Clinical Antiarrhythmic Agents.
Year : 2019
Volume : 62
Issue : 22
First Page : 10124
Last Page : 10143
Authors : Adebesin AM, Wesser T, Vijaykumar J, Konkel A, Paudyal MP, Lossie J, Zhu C, Westphal C, Puli N, Fischer R, Schunck WH, Falck JR.
Abstract : 17(R),18(S)-Epoxyeicosatetraenoic acid (EEQ) is a cytochrome P450 metabolite of eicosapentaenoic acid (EPA) and a powerful negative chronotrope with low nanomolar activity in a neonatal rat cardiomyocyte (NRCM) arrhythmia model. Prior studies identified oxamide 2b as a soluble epoxide hydrolase (sEH) stable replacement but unsuitable for in vivo applications due to limited oral bioavailability and metabolic stability. These ADME limitations have been addressed in an improved generation of negative chronotropes, e.g., 4 and 16, which were evaluated as potential clinical candidates.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
21.37
%
|
|
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
|
0.18
%
|
|
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
|
0.18
%
|
|
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.
|
Inhibition of CYP2C9 in human liver microsome using probe substrate measured after 20 mins in presence of NADPH by LC-MS/MS analysis
|
Homo sapiens
|
609.0
nM
|
|
Journal : J Med Chem
Title : Novel Human Urate Transporter 1 Inhibitors as Hypouricemic Drug Candidates with Favorable Druggability.
Year : 2020
Volume : 63
Issue : 19.0
First Page : 10829
Last Page : 10854
Authors : Zhao T,Meng Q,Sun Z,Chen Y,Ai W,Zhao Z,Kang D,Dong Y,Liang R,Wu T,Pang J,Liu X,Zhan P
Abstract : Lesinurad, a human urate transporter 1 (URAT1) inhibitor approved as a medication for the treatment of hyperuricemia associated with gout in 2015, can cause liver and renal toxicity. Here, we modified all three structural components of lesinurad by applying scaffold hopping, bioisosterism, and substituent-decorating strategies. In a mouse model of acute hyperuricemia, 21 of the synthesized compounds showed increased serum uric acid (SUA)-reducing activity; SUA was about 4-fold lower in animals treated with 44, 54, and 83 compared with lesinurad or benzbromarone. In the URAT1 inhibition assay, 44 was over 8-fold more potent than lesinurad (IC: 1.57 μM vs 13.21 μM). Notably, 83 also displayed potent inhibitory activity (IC = 31.73 μM) against GLUT9. Furthermore, we also preliminarily explored the effect of chirality on the potency of the promising derivatives 44 and 54. Compounds 44, 54, and 83 showed favorable drug-like pharmacokinetics and appear to be promising candidates for the treatment of hyperuricemia and gout.
|
Inhibition of CYP2C9 in human liver microsomes at 10 uM using diclofenac as substrate preincubated for 5 mins followed by NADPH addition and measured after 20 mins by LC-MS/MS analysis relative to control
|
Homo sapiens
|
82.0
%
|
|
Journal : J Med Chem
Title : Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.
Year : 2016
Volume : 59
Issue : 23.0
First Page : 10498
Last Page : 10519
Authors : Jiang F,Wang HJ,Jin YH,Zhang Q,Wang ZH,Jia JM,Liu F,Wang L,Bao QC,Li DD,You QD,Xu XL
Abstract : Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.
|
Inhibition of CYP2C9 in human liver microsomes after 20 mins by LC-MS/MS analysis
|
Homo sapiens
|
770.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis.
Year : 2020
Volume : 63
Issue : 17
First Page : 9316
Last Page : 9339
Authors : Zhao H,Wang B,Fu L,Li G,Lu H,Liu Y,Sheng L,Li Y,Zhang B,Lu Y,Ma C,Huang H,Zhang D,Lu Y
Abstract : Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone 19c with improved anti-TB activity and safety profile through a focused lead optimization effort. Compound 19c displayed superior in vivo efficacy in a mouse TB infection model compared to linezolid and sutezolid. The druggability of compound 19c was demonstrated in a panel of assays including microsomal stability, cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics in animals. Compound 19c demonstrated an excellent safety profile in a battery of safety assays, including mitochondrial protein synthesis, hERG K, hCav1.2, and Nav1.5 channels, monoamine oxidase, and genotoxicity. In a 4 week repeated dose toxicology study in rats, 19c appeared to have less bone marrow suppression than linezolid, which has been a major liability of the oxazolidinone class.
|
Inhibition of CYP2C9 (unknown origin) at 0.5 uM relative to control
|
Homo sapiens
|
48.3
%
|
|
Journal : Bioorg Med Chem Lett
Title : The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition.
Year : 2021
Volume : 40
First Page : 127924
Last Page : 127924
Authors : Chen H,Wang B,Li P,Yan H,Li G,Huang H,Lu Y
Abstract : In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
|
Inhibition of CYP2C9 (unknown origin)
|
Homo sapiens
|
630.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition.
Year : 2021
Volume : 40
First Page : 127924
Last Page : 127924
Authors : Chen H,Wang B,Li P,Yan H,Li G,Huang H,Lu Y
Abstract : In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
|
Cytotoxicity against African green monkey Vero cells assessed as reduction in cell viability
|
Chlorocebus sabaeus
|
64.0
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition.
Year : 2021
Volume : 40
First Page : 127924
Last Page : 127924
Authors : Chen H,Wang B,Li P,Yan H,Li G,Huang H,Lu Y
Abstract : In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate incubated for 5 mins followed by NADPH addition and measured after 20 mins by LC-MS/MS analysis
|
Homo sapiens
|
893.0
nM
|
|
Journal : Eur J Med Chem
Title : Substituted benzothiophene and benzofuran derivatives as a novel class of bone morphogenetic Protein-2 upregulators: Synthesis, anti-osteoporosis efficacies in ovariectomized rats and a zebrafish model, and ADME properties.
Year : 2020
Volume : 200
First Page : 112465
Last Page : 112465
Authors : Xue ST,Zhang L,Xie ZS,Jin J,Guo HF,Yi H,Liu ZY,Li ZR
Abstract : The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.
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Inhibition of CYP2C9 in human liver microsomes using Diclofenac as substrate measured after 20 mins by LC-MS/MS analysis
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Homo sapiens
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367.0
nM
|
|
|
Inhibition of CYP2C9 in human liver Microsome using diclofenac as substrate preincubated for 10 mins followed by NADPH addition and further incubated for 10 mins as substrate by LC-MS/MS analysis relative to control
|
Homo sapiens
|
84.5
%
|
|
|
Inhibition of CYP2C9 in human liver microsomes using diclofenac as substrate in presence of NADPH incubated for 10 mins by LC-MS/MS analysis
|
Homo sapiens
|
586.0
nM
|
|
|
Inhibition of CYP2C9 in human liver microsome using tolbutamide as substrate
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Homo sapiens
|
641.0
nM
|
|
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Inhibition of CYP2C9 (unknown origin) at 1 uM using diclofenac as substrate relative to control
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Homo sapiens
|
79.9
%
|
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