|
Percent inhibition of 14C]cholesterol absorption into plasma using cholesterol absorption assay in rats at the dose of 10 ug/Kg
|
Rattus norvegicus
|
74.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors.
Year : 2002
Volume : 12
Issue : 3
First Page : 315
Last Page : 318
Authors : Burnett DA, Caplen MA, Browne ME, Zhau H, Altmann SW, Davis HR, Clader JW.
Abstract : Fluorescent analogues of the cholesterol absorption inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA).
|
Percent inhibition of 14C]cholesterol absorption into plasma using cholesterol absorption assay in rats at the dose of 3 ug/Kg
|
Rattus norvegicus
|
63.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors.
Year : 2002
Volume : 12
Issue : 3
First Page : 315
Last Page : 318
Authors : Burnett DA, Caplen MA, Browne ME, Zhau H, Altmann SW, Davis HR, Clader JW.
Abstract : Fluorescent analogues of the cholesterol absorption inhibitor (CAI), Sch 58235, have been designed and synthesized as single enantiomers. Biological testing reveals that they are potent CAIs and are suitable tools for the investigation of the azetidinone CAI mechanism of action (MOA).
|
Percent inhibition against cholesterol absorption in brush border membrane vesicle using rabbit small intestine at concentration of 6 uM
|
Oryctolagus cuniculus
|
16.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and in vitro evaluation of inhibitors of intestinal cholesterol absorption.
Year : 2005
Volume : 48
Issue : 19
First Page : 6035
Last Page : 6053
Authors : Kvaernø L, Werder M, Hauser H, Carreira EM.
Abstract : We have utilized our recently developed in vitro assay to address two key questions in the design of small-molecule cholesterol absorption inhibitors using ezetimibe, the only drug yet approved for the inhibition of cholesterol absorption in the small intestine, as a starting point: (1) the role of glycosylation and (2) the importance of the beta-lactam scaffold of ezetimibe for inhibitory activity. A wide range of nonhydrolyzable phenolic glycosides of ezetimibe were synthesized and demonstrated to be active inhibitors of cholesterol absorption using the brush border membrane vesicle assay. The analogous azetidines provided access to a variety of inhibitors in vitro, suggesting that the beta-lactam of ezetimibe merely serves as a ring scaffold to appropriately position the required substituents. Our findings highlight several promising strategies for the design of alternative small-molecule cholesterol absorption inhibitors that could ultimately be useful in preventing cardiovascular disease by lowering blood cholesterol levels.
|
Displacement of [3H]ezetimibe-glucuronide from NPC1L1 in Sprague-Dawley rat brush border membrane
|
Rattus norvegicus
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substituted oxazolidinones as novel NPC1L1 ligands for the inhibition of cholesterol absorption.
Year : 2008
Volume : 18
Issue : 2
First Page : 546
Last Page : 553
Authors : Pfefferkorn JA, Larsen SD, Van Huis C, Sorenson R, Barton T, Winters T, Auerbach B, Wu C, Wolfram TJ, Cai H, Welch K, Esmaiel N, Davis J, Bousley R, Olsen K, Mueller SB, Mertz T.
Abstract : Cholesterol absorption inhibition (CAI) represents an important treatment option for hypercholesterolemia. Herein, we report the design and evaluation of a series of substituted oxazolidinones as ligands for the Niemann Pick C1 Like 1 (NPC1L1) protein, a key mediator of cholesterol transport. Novel analogs were initially evaluated in a brush border membrane NPC1L1 binding assay; subsequently, promising compounds were evaluated in vivo for acute inhibition of cholesterol absorption. These studies identified analogs with low micromolar NPC1L1 binding affinity and acute in vivo efficacy of >50% absorption inhibition at 3mg/kg.
|
Inhibition of cholesterol absorption in chow fed hamster at 3 mg/kg, po
|
Cricetinae
|
-89.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substituted oxazolidinones as novel NPC1L1 ligands for the inhibition of cholesterol absorption.
Year : 2008
Volume : 18
Issue : 2
First Page : 546
Last Page : 553
Authors : Pfefferkorn JA, Larsen SD, Van Huis C, Sorenson R, Barton T, Winters T, Auerbach B, Wu C, Wolfram TJ, Cai H, Welch K, Esmaiel N, Davis J, Bousley R, Olsen K, Mueller SB, Mertz T.
Abstract : Cholesterol absorption inhibition (CAI) represents an important treatment option for hypercholesterolemia. Herein, we report the design and evaluation of a series of substituted oxazolidinones as ligands for the Niemann Pick C1 Like 1 (NPC1L1) protein, a key mediator of cholesterol transport. Novel analogs were initially evaluated in a brush border membrane NPC1L1 binding assay; subsequently, promising compounds were evaluated in vivo for acute inhibition of cholesterol absorption. These studies identified analogs with low micromolar NPC1L1 binding affinity and acute in vivo efficacy of >50% absorption inhibition at 3mg/kg.
|
Inhibition of [3H]cholesterol absorption in C57BL/6 mouse plasma at 1 mg/kg, po after 1.5 hrs
|
Mus musculus
|
7.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Spiroimidazolidinone NPC1L1 inhibitors. Part 2: structure-activity studies and in vivo efficacy.
Year : 2010
Volume : 20
Issue : 23
First Page : 6929
Last Page : 6932
Authors : Howell KL, DeVita RJ, Garcia-Calvo M, Meurer RD, Lisnock J, Bull HG, McMasters DR, McCann ME, Mills SG.
Abstract : Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
|
Inhibition of [3H]cholesterol absorption in C57BL/6 mouse plasma at 1 mg/kg, po after 5 hrs
|
Mus musculus
|
90.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Spiroimidazolidinone NPC1L1 inhibitors. Part 2: structure-activity studies and in vivo efficacy.
Year : 2010
Volume : 20
Issue : 23
First Page : 6929
Last Page : 6932
Authors : Howell KL, DeVita RJ, Garcia-Calvo M, Meurer RD, Lisnock J, Bull HG, McMasters DR, McCann ME, Mills SG.
Abstract : Ezetimibe (Zetia®), a cholesterol-absorption inhibitor (CAI) approved by the FDA for the treatment of hypercholesterolemia, is believed to target the intestine protein Niemann-Pick C1-Like 1 (NPC1L1) or its pathway. A spiroimidazolidinone NPC1L1 inhibitor identified by virtual screening showed moderate binding activity but was not efficacious in an in vivo rodent model of cholesterol absorption. Synthesis of analogs established the structure-activity relationships for binding activity, and resulted in compounds with in vivo efficacy, including 24, which inhibited plasma cholesterol absorption by 67% in the mouse, thereby providing proof-of-concept that non-β-lactams can be effective CAIs.
|
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
|
55.5
%
|
|
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
|
1.5
%
|
|
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
|
-8.9
%
|
|
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 sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
51.36
%
|
|
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
|
30.63
%
|
|
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.
|
In vivo inhibition of acute [3H]cholesterol absorption in C57BL/6 mouse plasma at 10 mg/kg/day, po for 2 days before cholesterol administration measured 4 hrs post cholesterol administration relative to vehicle-treated control
|
Mus musculus
|
60.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
Year : 2014
Volume : 87
First Page : 722
Last Page : 734
Authors : Dražić T, Molčanov K, Sachdev V, Malnar M, Hećimović S, Patankar JV, Obrowsky S, Levak-Frank S, Habuš I, Kratky D.
Abstract : Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.
|
In vivo inhibition of acute [3H]cholesterol absorption in C57BL/6 mouse duodenum at 10 mg/kg/day, po for 2 days before cholesterol administration measured 4 hrs post cholesterol administration relative to vehicle-treated control
|
Mus musculus
|
65.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
Year : 2014
Volume : 87
First Page : 722
Last Page : 734
Authors : Dražić T, Molčanov K, Sachdev V, Malnar M, Hećimović S, Patankar JV, Obrowsky S, Levak-Frank S, Habuš I, Kratky D.
Abstract : Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.
|
In vivo inhibition of acute [3H]cholesterol absorption in C57BL/6 mouse jejunum at 10 mg/kg/day, po for 2 days before cholesterol administration measured 4 hrs post cholesterol administration relative to vehicle-treated control
|
Mus musculus
|
61.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
Year : 2014
Volume : 87
First Page : 722
Last Page : 734
Authors : Dražić T, Molčanov K, Sachdev V, Malnar M, Hećimović S, Patankar JV, Obrowsky S, Levak-Frank S, Habuš I, Kratky D.
Abstract : Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.
|
In vivo inhibition of acute [3H]cholesterol absorption in C57BL/6 mouse ileum at 10 mg/kg/day, po for 2 days before cholesterol administration measured 4 hrs post cholesterol administration relative to vehicle-treated control
|
Mus musculus
|
47.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
Year : 2014
Volume : 87
First Page : 722
Last Page : 734
Authors : Dražić T, Molčanov K, Sachdev V, Malnar M, Hećimović S, Patankar JV, Obrowsky S, Levak-Frank S, Habuš I, Kratky D.
Abstract : Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.
|
In vivo inhibition of acute [3H]cholesterol absorption in C57BL/6 mouse liver at 10 mg/kg/day, po for 2 days before cholesterol administration measured 4 hrs post cholesterol administration relative to vehicle-treated control
|
Mus musculus
|
52.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Novel amino-β-lactam derivatives as potent cholesterol absorption inhibitors.
Year : 2014
Volume : 87
First Page : 722
Last Page : 734
Authors : Dražić T, Molčanov K, Sachdev V, Malnar M, Hećimović S, Patankar JV, Obrowsky S, Levak-Frank S, Habuš I, Kratky D.
Abstract : Two new trans-(3R,4R)-amino-β-lactam derivatives and their diastereoisomeric mixtures were synthesized as ezetimibe bioisosteres and tested in in vitro and in vivo experiments as novel β-lactam cholesterol absorption inhibitors. Both compounds exhibited low cytotoxicity in MDCKII, hNPC1L1/MDCKII, and HepG2 cell lines and potent inhibitory effect in hNPC1L1/MDCKII cells. In addition, these compounds markedly reduced cholesterol absorption in mice, resulting in reduced cholesterol concentrations in plasma, liver, and intestine. We determined the crystal structure of one amino-β-lactam derivative to establish unambiguously both the absolute and relative configuration at the new stereogenic centre C17, which was assigned to be S. The pKa values for both compounds are 9.35, implying that the amino-β-lactam derivatives and their diastereoisomeric mixtures are in form of ammonium salt in blood and the intestine. The IC50 value for the diastereoisomeric mixture is 60 μM. In vivo, it efficiently inhibited cholesterol absorption comparable to ezetimibe.
|
Inhibition of human NPC1L1 transfected in MDCK2 cells assessed as [3H]cholesterol uptake at 60 uM after 1 hr by liquid scintillation counting analysis
|
Homo sapiens
|
45.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.
Year : 2015
Volume : 23
Issue : 10
First Page : 2353
Last Page : 2359
Authors : Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D.
Abstract : The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
|
Inhibition of [3H]cholesterol uptake in C57BL/6 mouse liver at 20 mg/kg/day, po for 2 days measured 4 hrs post last dose on day 2
|
Mus musculus
|
53.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.
Year : 2015
Volume : 23
Issue : 10
First Page : 2353
Last Page : 2359
Authors : Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D.
Abstract : The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
|
Inhibition of [3H]cholesterol uptake in C57BL/6 mouse duodenum at 20 mg/kg/day, po for 2 days measured 4 hrs post last dose on day 2
|
Mus musculus
|
60.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.
Year : 2015
Volume : 23
Issue : 10
First Page : 2353
Last Page : 2359
Authors : Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D.
Abstract : The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
|
Inhibition of [3H]cholesterol uptake in C57BL/6 mouse jejunum at 20 mg/kg/day, po for 2 days measured 4 hrs post last dose on day 2
|
Mus musculus
|
52.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.
Year : 2015
Volume : 23
Issue : 10
First Page : 2353
Last Page : 2359
Authors : Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D.
Abstract : The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
|
Inhibition of [3H]cholesterol uptake in C57BL/6 mouse ileum at 20 mg/kg/day, po for 2 days measured 4 hrs post last dose on day 2
|
Mus musculus
|
44.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel amide amino-β-lactam derivatives as cholesterol absorption inhibitors.
Year : 2015
Volume : 23
Issue : 10
First Page : 2353
Last Page : 2359
Authors : Dražić T, Sachdev V, Leopold C, Patankar JV, Malnar M, Hećimović S, Levak-Frank S, Habuš I, Kratky D.
Abstract : The β-lactam cholesterol absorption inhibitor ezetimibe is so far the only representative of this class of compounds on the market today. The goal of this work was to synthesize new amide ezetimibe analogs from trans-3-amino-(3R,4R)-β-lactam and to test their cytotoxicity and activity as cholesterol absorption inhibitors. We synthesized six new amide ezetimibe analogs. All new compounds exhibited low toxicity in MDCKIIwt, hNPC1L1/MDCKII and HepG2 cell lines and showed significant inhibition of cholesterol uptake in hNPC1L1/MDCKII cells. In addition, we determined the activity of the three compounds to inhibit cholesterol absorption in vivo. Our results demonstrate that these compounds considerably reduce cholesterol concentrations in liver and small intestine of mice. Thus, our newly synthesized amide ezetimibe analogs are cholesterol absorption inhibitors in vitro and in vivo.
|
Inhibition of NPC1L1 in human Caco2 cells assessed as decrease in cholesterol uptake at 100 uM preincubated for 24 hrs followed by stigmosterol substrate addition measured after 24 hrs by HPLC method relative to control
|
Homo sapiens
|
51.3
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 1H-pyrrole-2,5-dione derivatives as cholesterol absorption inhibitors for suppressing the formation of foam cells and inflammatory response.
Year : 2018
Volume : 26
Issue : 8
First Page : 1435
Last Page : 1447
Authors : Yuan X, Xia Y, Lu P, Zhu L, Zhong Y, Wang Y.
Abstract : Excess lipid accumulation in the arterial intima and formation of macrophage-derived foam cells in the plaque could cause atherosclerotic lesion. Cholesterol absorption inhibitors could suppress the lipid accumulation of human macrophage, inflammatory response and the development of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized as cholesterol absorption inhibitor and tested in in vitro experiments. One of the most active inhibitors, compound 20 exhibited stronger in vitro cholesterol absorption activity than ezetimibe, no cytotoxicity in HEK293 and RAW264.7 cell lines and satisfied lipophilicity. The further study indicated that 20 could inhibit lipid accumulation of macrophage and reduce the secretion of LDH, MDA, TNF-α and ROS in a concentration-dependent manner. In conclusion, as a novel and potent cholesterol absorption inhibitor, compound 20 could suppress the formation of foam cells and inflammatory response.
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Inhibition of NPC1L1 in mouse RAW264.7 cells assessed as decrease in choleserol-D7 absorption at 30 uM after 72 hrs by LC-MS/MS analysis relative to control
|
Mus musculus
|
80.3
%
|
|
Journal : Bioorg Med Chem
Title : Synthesis and evaluation of 1H-pyrrole-2,5-dione derivatives as cholesterol absorption inhibitors for suppressing the formation of foam cells and inflammatory response.
Year : 2018
Volume : 26
Issue : 8
First Page : 1435
Last Page : 1447
Authors : Yuan X, Xia Y, Lu P, Zhu L, Zhong Y, Wang Y.
Abstract : Excess lipid accumulation in the arterial intima and formation of macrophage-derived foam cells in the plaque could cause atherosclerotic lesion. Cholesterol absorption inhibitors could suppress the lipid accumulation of human macrophage, inflammatory response and the development of atherosclerosis. In this research, a series of 1H-pyrrole-2,5-dione derivatives were synthesized as cholesterol absorption inhibitor and tested in in vitro experiments. One of the most active inhibitors, compound 20 exhibited stronger in vitro cholesterol absorption activity than ezetimibe, no cytotoxicity in HEK293 and RAW264.7 cell lines and satisfied lipophilicity. The further study indicated that 20 could inhibit lipid accumulation of macrophage and reduce the secretion of LDH, MDA, TNF-α and ROS in a concentration-dependent manner. In conclusion, as a novel and potent cholesterol absorption inhibitor, compound 20 could suppress the formation of foam cells and inflammatory response.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
5.57
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-0.7
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
2.21
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
24.27
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
11.71
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
-1.0
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-1.78
%
|
|
|
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
|
35.64
%
|
|
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 recombinant human GALNS expressed in Pichia pastoris at 10 uM using 4-methylumbelliferyl-beta-D-galactopyranoside-6-sulfate as substrate measured after 18 hrs by fluorescence assay relative to control
|
Homo sapiens
|
40.0
%
|
|
Journal : J Med Chem
Title : Identification of Ezetimibe and Pranlukast as Pharmacological Chaperones for the Treatment of the Rare Disease Mucopolysaccharidosis Type IVA.
Year : 2019
Volume : 62
Issue : 13
First Page : 6175
Last Page : 6189
Authors : Alméciga-Diaz CJ, Hidalgo OA, Olarte-Avellaneda S, Rodríguez-López A, Guzman E, Garzón R, Pimentel-Vera LN, Puentes-Tellez MA, Rojas-Rodriguez AF, Gorshkov K, Li R, Zheng W.
Abstract : Mucopolysaccharidosis type IVA (MPS IVA) is a rare disease caused by mutations in the gene encoding the lysosomal enzyme <i>N</i>-acetylgalactosamine-6-sulfate sulfatase (GALNS). We report here two GALNS pharmacological chaperones, ezetimibe and pranlukast, identified by molecular docking-based virtual screening. These compounds bound to the active cavity of GALNS and increased its thermal stability as well as the production of recombinant GALNS in bacteria, yeast, and HEK293 cells. MPS IVA fibroblasts treated with these chaperones exhibited increases in GALNS protein and enzyme activity and reduced the size of enlarged lysosomes. Abnormalities in autophagy markers p62 and LC3B-II were alleviated by ezetimibe and pranlukast. Combined treatment of recombinant GALNS with ezetimibe or pranlukast produced an additive effect. Altogether, the results demonstrate that ezetimibe and pranlukast can increase the yield of recombinant GALNS and be used as a monotherapy or combination therapy to improve the therapeutic efficacy of MPS IVA enzyme replacement therapy.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.81
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.14
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-0.05255
%
|
|
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
|
1.05
%
|
|
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
|
0.03
%
|
|
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
|
1.85
%
|
|
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
|
1.85
%
|
|
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
|
1.05
%
|
|
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
|
0.03
%
|
|
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 PTL (unknown origin) at 50 uM relative to control
|
Homo sapiens
|
23.5
%
|
|
