|
Inhibition of human recombinant rennin in buffer assessed as accumulation of angiotensin 1 using human tetradecapeptide by immunoassay
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.
Year : 2009
Volume : 52
Issue : 12
First Page : 3689
Last Page : 3702
Authors : Bezençon O, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf O, Grisostomi C, Boss C, Prade L, Delahaye S, Treiber A, Strickner P, Binkert C, Hess P, Steiner B, Fischli W.
Abstract : Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
|
Inhibition of human recombinant renin
|
Homo sapiens
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and optimization of renin inhibitors: Orally bioavailable alkyl amines.
Year : 2009
Volume : 19
Issue : 13
First Page : 3541
Last Page : 3545
Authors : Tice CM, Xu Z, Yuan J, Simpson RD, Cacatian ST, Flaherty PT, Zhao W, Guo J, Ishchenko A, Singh SB, Wu Z, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Müller D, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
|
Inhibition of human recombinant renin in presence of human plasma by competitive radioimmunoassay
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and optimization of renin inhibitors: Orally bioavailable alkyl amines.
Year : 2009
Volume : 19
Issue : 13
First Page : 3541
Last Page : 3545
Authors : Tice CM, Xu Z, Yuan J, Simpson RD, Cacatian ST, Flaherty PT, Zhao W, Guo J, Ishchenko A, Singh SB, Wu Z, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Müller D, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
|
Inhibition of purified recombinant human renin
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The P1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin.
Year : 2009
Volume : 19
Issue : 16
First Page : 4863
Last Page : 4867
Authors : Yamaguchi Y, Menear K, Cohen NC, Mah R, Cumin F, Schnell C, Wood JM, Maibaum J.
Abstract : Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P(1) motif were designed based on initial lead structures 1 and aliskiren (2). (P(3)-P(1))-Benzamide derivatives such as 9a and 34, as well as the corresponding P(1) basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.
|
Inhibition of human plasma renin
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The P1N-isopropyl motif bearing hydroxyethylene dipeptide isostere analogues of aliskiren are in vitro potent inhibitors of the human aspartyl protease renin.
Year : 2009
Volume : 19
Issue : 16
First Page : 4863
Last Page : 4867
Authors : Yamaguchi Y, Menear K, Cohen NC, Mah R, Cumin F, Schnell C, Wood JM, Maibaum J.
Abstract : Novel nonpeptide small molecule renin inhibitors bearing an N-isopropyl P(1) motif were designed based on initial lead structures 1 and aliskiren (2). (P(3)-P(1))-Benzamide derivatives such as 9a and 34, as well as the corresponding P(1) basic tertiary amine derivatives 10 and 35 were found to display low nanomolar inhibition against human renin in vitro.
|
Inhibition of trypsin-activated human recombinant renin
|
Homo sapiens
|
0.53
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of orally bioavailable alkyl amine renin inhibitors.
Year : 2010
Volume : 20
Issue : 2
First Page : 694
Last Page : 699
Authors : Xu Z, Cacatian S, Yuan J, Simpson RD, Jia L, Zhao W, Tice CM, Flaherty PT, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Bentley R, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
|
Inhibition of human recombinant renin assessed as decrease in plasma renin activity by competitive radioimmunoassay in presence of human plasma
|
Homo sapiens
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Optimization of orally bioavailable alkyl amine renin inhibitors.
Year : 2010
Volume : 20
Issue : 2
First Page : 694
Last Page : 699
Authors : Xu Z, Cacatian S, Yuan J, Simpson RD, Jia L, Zhao W, Tice CM, Flaherty PT, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Scott BB, Bukhtiyarov Y, Berbaum J, Mason J, Panemangalore R, Cappiello MG, Bentley R, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
|
Inhibition of renin in plasma
|
None
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Direct renin inhibitors as a new therapy for hypertension.
Year : 2010
Volume : 53
Issue : 21
First Page : 7490
Last Page : 7520
Authors : Webb RL, Schiering N, Sedrani R, Maibaum J.
|
Inhibition of rat renin
|
Rattus norvegicus
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Direct renin inhibitors as a new therapy for hypertension.
Year : 2010
Volume : 53
Issue : 21
First Page : 7490
Last Page : 7520
Authors : Webb RL, Schiering N, Sedrani R, Maibaum J.
|
Inhibition of mouse renin
|
Mus musculus
|
4.5
nM
|
|
Journal : J. Med. Chem.
Title : Direct renin inhibitors as a new therapy for hypertension.
Year : 2010
Volume : 53
Issue : 21
First Page : 7490
Last Page : 7520
Authors : Webb RL, Schiering N, Sedrani R, Maibaum J.
|
Inhibition of rabbit renin
|
Oryctolagus cuniculus
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Direct renin inhibitors as a new therapy for hypertension.
Year : 2010
Volume : 53
Issue : 21
First Page : 7490
Last Page : 7520
Authors : Webb RL, Schiering N, Sedrani R, Maibaum J.
|
Inhibition of human renin
|
Homo sapiens
|
0.6
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Potential virtual lead identification in the discovery of renin inhibitors: application of ligand and structure-based pharmacophore modeling approaches.
Year : 2011
Volume : 46
Issue : 6
First Page : 2469
Last Page : 2476
Authors : Thangapandian S, John S, Sakkiah S, Lee KW.
Abstract : Renin, an enzyme by cleaving angiotensinogen to angiotensin-I, controls the first and rate-limiting step of renin-angiotensin system that is associated with blood pressure. Thus Ligand and structure-based pharmacophore models were developed in this study to identify new potential leads inhibiting this rate-limiting enzyme as an efficient way to treat blood pressure. X-ray predicted binding modes of most active compounds were used in ligand-based approach whereas the 3D structural information of renin was used in structure-based approach. Pharmacophore models were validated using various methods and utilized in database searching to identify potential hits. Drug-like filters and molecular docking studies led us identifying the final hits to be employed in designing new class of future renin inhibitors.
|
Inhibition of renin measured every 30 secs for 15 mins by fluorimetric analysis
|
None
|
2.21
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, biological evaluation and docking studies of octane-carboxamide based renin inhibitors with extended segments toward S3' site of renin.
Year : 2011
Volume : 19
Issue : 14
First Page : 4238
Last Page : 4249
Authors : Wu Y, Shi C, Sun X, Wu X, Sun H.
Abstract : Eighteen octane-carboxamide based renin inhibitors with extended segments for mimicking P3' unit of angiotensinogen have been synthesized. The biological evaluation identified novel renin inhibitors with more potent activity than aliskiren. Molecular docking studies showed that the extended amide-tails matched the P3' position of angiotensinogen and exerted interactions with the S3' site of renin. An unexpected π-π stacking interaction was observed during docking study for compound 9r, which could be a reasonable explanation for the outstanding potency of this compound. Further study is in progress to reveal a feasibility for developing novel renin inhibitors based on the possible non-classical interactions between the ligands and the new subsite of renin.
|
Inhibition of human recombinant renin using DABCYL-gamma-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-EDANS as substrate for 60 mins by fluorimetry
|
Homo sapiens
|
0.4
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
Year : 2011
Volume : 2
Issue : 10
First Page : 747
Last Page : 751
Authors : Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
|
Inhibition of human recombinant renin using H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-OH as substrate assessed as formation of angiotensin1 product after 2 hrs by competive radioimmunoassay
|
Homo sapiens
|
0.53
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
Year : 2011
Volume : 2
Issue : 10
First Page : 747
Last Page : 751
Authors : Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
|
Inhibition of renin in human plasma assessed as formation of angiotensin1 product after 90 mins by competitive radioimmunoassay
|
Homo sapiens
|
0.65
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
Year : 2011
Volume : 2
Issue : 10
First Page : 747
Last Page : 751
Authors : Jia L, Simpson RD, Yuan J, Xu Z, Zhao W, Cacatian S, Tice CM, Guo J, Ishchenko A, Singh SB, Wu Z, McKeever BM, Bukhtiyarov Y, Johnson JA, Doe CP, Harrison RK, McGeehan GM, Dillard LW, Baldwin JJ, Claremon DA.
Abstract : Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
|
Inhibition of HIV1 recombinant protease using Lys-Ala-Arg-Val-Nle-Nph-Glu-Ala-Nle-NH2 as substrate by spectrophotometric analysis
|
Human immunodeficiency virus 1
|
76.5
nM
|
|
Journal : J. Med. Chem.
Title : Dual inhibitors for aspartic proteases HIV-1 PR and renin: advancements in AIDS-hypertension-diabetes linkage via molecular dynamics, inhibition assays, and binding free energy calculations.
Year : 2012
Volume : 55
Issue : 12
First Page : 5784
Last Page : 5796
Authors : Tzoupis H, Leonis G, Megariotis G, Supuran CT, Mavromoustakos T, Papadopoulos MG.
Abstract : Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,exp)= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy.
|
Inhibition of human renin
|
Homo sapiens
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Dual inhibitors for aspartic proteases HIV-1 PR and renin: advancements in AIDS-hypertension-diabetes linkage via molecular dynamics, inhibition assays, and binding free energy calculations.
Year : 2012
Volume : 55
Issue : 12
First Page : 5784
Last Page : 5796
Authors : Tzoupis H, Leonis G, Megariotis G, Supuran CT, Mavromoustakos T, Papadopoulos MG.
Abstract : Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,exp)= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy.
|
Inhibition of renin (unknown origin)
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.
Year : 2015
Volume : 25
Issue : 7
First Page : 1592
Last Page : 1596
Authors : McKittrick BA, Caldwell JP, Bara T, Boykow G, Chintala M, Clader J, Czarniecki M, Courneya B, Duffy R, Fleming L, Giessert R, Greenlee WJ, Heap C, Hong L, Huang Y, Iserloh U, Josien H, Khan T, Korfmacher W, Liang X, Mazzola R, Mitra S, Moore K, Orth P, Rajagopalan M, Roy S, Sakwa S, Strickland C, Vaccaro H, Voigt J, Wang H, Wong J, Zhang R, Zych A.
Abstract : The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
|
Inhibition of CYP1A2 in human liver microsomes from 10 healthy donors at 200 uM aliskiren (SPP100)
|
Homo sapiens
|
15.2
%
|
|
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 CYP2C8 in human liver microsomes from 10 healthy donors at 200 uM aliskiren (SPP100)
|
Homo sapiens
|
4.5
%
|
|
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 CYP2C9 in human liver microsomes from 10 healthy donors at 200 uM aliskiren (SPP100)
|
Homo sapiens
|
32.1
%
|
|
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 CYP2C19 in human liver microsomes from 10 healthy donors at 200 uM aliskiren (SPP100)
|
Homo sapiens
|
42.5
%
|
|
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 CYP2D6 in human liver microsomes from 10 healthy donors at 200 uM aliskiren (SPP100)
|
Homo sapiens
|
32.9
%
|
|
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 CYP2E1 in human liver microsomes from 10 healthy donors at 200 uM aliskiren (SPP100)
|
Homo sapiens
|
-12.8
%
|
|
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 CYP3A4/5 in human liver microsomes from 10 healthy donors at 10 uM aliskiren (SPP100)
|
Homo sapiens
|
-16.6
%
|
|
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 20 uM SPP100 on 502 Pmoles of cDNA-derived CYP1A2 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
2.5
%
|
|
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 20 uM SPP100 on 545 Pmoles of cDNA-derived CYP1A2 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-5.8
%
|
|
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 20 uM SPP100 on 489 Pmoles of cDNA-derived CYP1A2 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
5.0
%
|
|
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 200 uM SPP100 on 484 Pmoles of cDNA-derived CYP1A2 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
6.0
%
|
|
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 200 uM SPP100 on 548 Pmoles of cDNA-derived CYP1A2 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-6.4
%
|
|
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 200 uM SPP100 on 578 Pmoles of cDNA-derived CYP1A2 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-12.4
%
|
|
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 20 uM SPP100 on 39 Pmoles of cDNA-derived CYP2A6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-2.1
%
|
|
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 20 uM SPP100 on 37 Pmoles of cDNA-derived CYP2A6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
2.6
%
|
|
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 20 uM SPP100 on 37 Pmoles of cDNA-derived CYP2A6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
2.6
%
|
|
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 200 uM SPP100 on 37 Pmoles of cDNA-derived CYP2A6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
2.6
%
|
|
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 200 uM SPP100 on 37 Pmoles of cDNA-derived CYP2A6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
2.6
%
|
|
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 200 uM SPP100 on 34 Pmoles of cDNA-derived CYP2A6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
10.5
%
|
|
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 20 uM SPP100 on 227 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
13.1
%
|
|
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 20 uM SPP100 on 259 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
0.9
%
|
|
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 20 uM SPP100 on 258 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
1.3
%
|
|
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 200 uM SPP100 on 222 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
14.9
%
|
|
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 200 uM SPP100 on 201 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
23.0
%
|
|
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 200 uM SPP100 on 220 Pmoles of cDNA-derived CYP2C9 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
15.8
%
|
|
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 20 uM SPP100 on 1174 Pmoles of cDNA-derived CYP2C19 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-1.5
%
|
|
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 20 uM SPP100 on 1131 Pmoles of cDNA-derived CYP2C19 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
5.1
%
|
|
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 20 uM SPP100 on 1214 Pmoles of cDNA-derived CYP2C19 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-1.9
%
|
|
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 200 uM SPP100 on 1375 Pmoles of cDNA-derived CYP2C19 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
-15.4
%
|
|
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 200 uM SPP100 on 1156 Pmoles of cDNA-derived CYP2C19 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
3.0
%
|
|
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 200 uM SPP100 on 1077 Pmoles of cDNA-derived CYP2C19 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
9.6
%
|
|
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 200 gM SPP100 on cDNA-derived CYP2D6 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
37.0
%
|
|
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 200 gM SPP100 on cDNA-derived CYP3A4 enzyme in microsome prepared from human lymphoblastoid cell line
|
Homo sapiens
|
11.0
%
|
|
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 recombinant renin preincubated for 30 mins followed by substrate addition measured after 15 mins by fluorescence analysis
|
Homo sapiens
|
2.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of highly potent renin inhibitors potentially interacting with the S3' subsite of renin.
Year : 2015
Volume : 103
First Page : 269
Last Page : 288
Authors : Sun X, Wen X, Chen YY, Shi C, Gao C, Wu Y, Wang LJ, Yang XH, Sun H.
Abstract : To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC₅₀ < 3 nM) were identified, among which compounds 38 (IC₅₀ = 0.9 nM) and 39 (IC₅₀ = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC₅₀ = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 μmol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.
|
Inhibition of recombinant human renin using 5-FAM/QXL 520 as substrate pretreated for 30 mins followed by substrate addition measured at 1 min interval for 15 mins by FRET assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.
Year : 2017
Volume : 25
Issue : 15
First Page : 3947
Last Page : 3963
Authors : Cloudsdale IS, Dickson JK, Barta TE, Grella BS, Smith ED, Kulp JL, Guarnieri F, Kulp JL.
Abstract : We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s<100nM) with good oral bioavailability (F>20-58%).
|
Inhibition of recombinant human renin
|
Homo sapiens
|
0.6
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.
Year : 2017
Volume : 25
Issue : 15
First Page : 3947
Last Page : 3963
Authors : Cloudsdale IS, Dickson JK, Barta TE, Grella BS, Smith ED, Kulp JL, Guarnieri F, Kulp JL.
Abstract : We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s<100nM) with good oral bioavailability (F>20-58%).
|
Inhibition of renin in human plasma by radioimmunoassay
|
Homo sapiens
|
0.84
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile.
Year : 2018
Volume : 26
Issue : 12
First Page : 3261
Last Page : 3286
Authors : Tokuhara H, Imaeda Y, Fukase Y, Iwanaga K, Taya N, Watanabe K, Kanagawa R, Matsuda K, Kajimoto Y, Kusumoto K, Kondo M, Snell G, Behnke CA, Kuroita T.
Abstract : We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.
|
Inhibition of renin in rat plasma
|
Rattus norvegicus
|
88.0
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile.
Year : 2018
Volume : 26
Issue : 12
First Page : 3261
Last Page : 3286
Authors : Tokuhara H, Imaeda Y, Fukase Y, Iwanaga K, Taya N, Watanabe K, Kanagawa R, Matsuda K, Kajimoto Y, Kusumoto K, Kondo M, Snell G, Behnke CA, Kuroita T.
Abstract : We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.
|
Inhibition of renin in monkey plasma
|
Macaca mulatta
|
1.2
nM
|
|
Journal : Bioorg Med Chem
Title : Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile.
Year : 2018
Volume : 26
Issue : 12
First Page : 3261
Last Page : 3286
Authors : Tokuhara H, Imaeda Y, Fukase Y, Iwanaga K, Taya N, Watanabe K, Kanagawa R, Matsuda K, Kajimoto Y, Kusumoto K, Kondo M, Snell G, Behnke CA, Kuroita T.
Abstract : We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.09
%
|
|
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
|
0.0
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.0
%
|
|
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.
