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Article: Nonclinical pharmacokinetics of BMS-292655, a water-soluble prodrug of the antifungal ravuconazole.

Knipe, Jay O / Mosure, Kathleen W

2008 Volume 29, Issue 5, Page(s) 270–279

Abstract: The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation ... ...

Abstract	The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion.
MeSH term(s)	Animals ; Antifungal Agents/pharmacokinetics ; Blood Proteins/metabolism ; Dogs ; Humans ; Hydrolysis ; In Vitro Techniques ; Macaca fascicularis ; Male ; Prodrugs/pharmacokinetics ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; Thiazoles/metabolism ; Thiazoles/pharmacokinetics ; Triazoles/metabolism ; Triazoles/pharmacokinetics
Chemical Substances	3-((phosphonooxy)methyl)-1-((2-(4-(4-cyanophenyl)-2-thiazolyl)-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)methyl)propoxy)methyl ester ; 3-(hydroxymethyl)-1-((2-(4-(4-cyanophenyl)-2-thia0zolyl)-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)methyl)propoxy)methyl ester ; Antifungal Agents ; Blood Proteins ; Prodrugs ; Thiazoles ; Triazoles ; ER 30346 (95YH599JWV)
Language	English
Publishing date	2008-05-21
Publishing country	England
Document type	Journal Article
ZDB-ID	603014-2
ISSN	1099-081X ; 0142-2782
ISSN (online)	1099-081X
ISSN	0142-2782
DOI	10.1002/bdd.612
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Article ; Online: Structure-activity relationships of 4-hydroxy-4-biaryl-proline acylsulfonamide tripeptides: A series of potent NS3 protease inhibitors for the treatment of hepatitis C virus.

Wang, Alan Xiangdong / Chen, Jie / Zhao, Qian / Sun, Li-Qiang / Friborg, Jacques / Yu, Fei / Hernandez, Dennis / Good, Andrew C / Klei, Herbert E / Rajamani, Ramkumar / Mosure, Kathy / Knipe, Jay O / Li, Danshi / Zhu, Jialong / Levesque, Paul C / McPhee, Fiona / Meanwell, Nicholas A / Scola, Paul M

Bioorganic & medicinal chemistry letters

2017 Volume 27, Issue 3, Page(s) 590–596

Abstract: The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information ... ...

Abstract	The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Half-Life ; Heart/drug effects ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Humans ; In Vitro Techniques ; Oligopeptides/chemistry ; Oligopeptides/pharmacokinetics ; Oligopeptides/pharmacology ; Proline/chemistry ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacokinetics ; Protease Inhibitors/pharmacology ; Rabbits ; Rats ; Structure-Activity Relationship ; Sulfonamides/chemistry ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; NS3 protein, hepatitis C virus ; Oligopeptides ; Protease Inhibitors ; Sulfonamides ; Viral Nonstructural Proteins ; Proline (9DLQ4CIU6V)
Language	English
Publishing date	2017--01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.12.013
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Article ; Online: The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease.

Bowsher, Michael / Hiebert, Sheldon / Li, Rongti / Wang, Alan X / Friborg, Jacques / Yu, Fei / Hernandez, Dennis / Wang, Ying-Kai / Klei, Herbert / Rajamani, Ramkumar / Mosure, Kathy / Knipe, Jay O / Meanwell, Nicholas A / McPhee, Fiona / Scola, Paul M

Bioorganic & medicinal chemistry letters

2017

Abstract: Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of ... ...

Abstract	Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.
Language	English
Publishing date	2017-11-03
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2017.11.005
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Article ; Online: Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor.

Mosure, Kathleen W / Knipe, Jay O / Browning, Marc / Arora, Vinod / Shu, Yue-Zhong / Phillip, Thomas / Mcphee, Fiona / Scola, Paul / Balakrishnan, Anand / Soars, Matthew G / Santone, Kenneth / Sinz, Michael

Journal of pharmaceutical sciences

2015 Volume 104, Issue 9, Page(s) 2813–2823

Abstract: Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive ... ...

Abstract	Asunaprevir (ASV; BMS-650032), a low nanomolar inhibitor of the hepatitis C virus (HCV) NS3 protease, is currently under development, in combination with other direct-acting antiviral (DAA) agents for the treatment of chronic HCV infection. Extensive nonclinical and pharmacokinetic studies have been conducted to characterize the ADME properties of ASV. ASV has a moderate to high clearance in preclinical species. In vitro reaction phenotyping studies demonstrated that the oxidative metabolism of ASV is primarily mediated via CYP3A4; however, studies in bile-duct cannulated rats and dogs suggest that biliary elimination may contribute to overall ASV clearance. ASV is shown to have hepatotropic disposition in all preclinical species tested (liver to plasma ratios >40). The translation of in vitro replicon potency to clinical viral load decline for a previous lead BMS-605339 was leveraged to predict a human dose of 2 mg BID for ASV. Clinical drug-drug interaction (DDI) studies have shown that at therapeutically relevant concentrations of ASV the potential for a DDI is minimal. The need for an interferon free treatment combined with ASV's initial clinical trial data support development of ASV as part of a fixed dose combination for the treatment of patients chronically infected with HCV genotype 1.
MeSH term(s)	ATP-Binding Cassette, Sub-Family B, Member 1/antagonists & inhibitors ; ATP-Binding Cassette, Sub-Family B, Member 1/metabolism ; Animals ; Antiviral Agents/pharmacokinetics ; Bile/metabolism ; Biological Availability ; Cytochrome P-450 CYP3A/metabolism ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Dogs ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Hepatocytes/metabolism ; Humans ; Isoquinolines/pharmacokinetics ; Liver/metabolism ; Macaca fascicularis ; Male ; Mice ; Microsomes, Liver/metabolism ; Oxidation-Reduction ; Protease Inhibitors/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Sulfonamides/pharmacokinetics ; Viral Nonstructural Proteins/antagonists & inhibitors
Chemical Substances	ATP-Binding Cassette, Sub-Family B, Member 1 ; Antiviral Agents ; Cytochrome P-450 Enzyme Inhibitors ; Isoquinolines ; NS3 protein, hepatitis C virus ; Protease Inhibitors ; Sulfonamides ; Viral Nonstructural Proteins ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; asunaprevir (S9X0KRJ00S)
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1002/jps.24356
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Article ; Online: Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase.

Bioorganic & medicinal chemistry letters

2017 Volume 27, Issue 15, Page(s) 3294–3300

Abstract: The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are ... ...

Abstract	The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Benzazepines/chemistry ; Benzazepines/pharmacokinetics ; Benzazepines/pharmacology ; Dogs ; Haplorhini ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Hepacivirus/metabolism ; Hepatitis C/drug therapy ; Hepatitis C/virology ; Humans ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/metabolism ; Rats ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Benzazepines ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2017-06-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2017.06.024
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Article: An automated liquid chromatography-mass spectrometry process to determine metabolic stability half-life and intrinsic clearance of drug candidates by substrate depletion.

McNaney, Colleen A / Drexler, Dieter M / Hnatyshyn, Serhiy Y / Zvyaga, Tatyana A / Knipe, Jay O / Belcastro, James V / Sanders, Mark

Assay and drug development technologies

2008 Volume 6, Issue 1, Page(s) 121–129

Abstract: An automated process is described for the detailed assessment of the in vitro metabolic stability properties of drug candidates in support of pharmaceutical property profiling. Compounds are incubated with liver microsomes using a robotic liquid handler. ...

Abstract	An automated process is described for the detailed assessment of the in vitro metabolic stability properties of drug candidates in support of pharmaceutical property profiling. Compounds are incubated with liver microsomes using a robotic liquid handler. Aliquots are taken at various time points, and the resulting samples are quantitatively analyzed by liquid chromatography-mass spectrometry utilizing ion trap mass spectrometers to determine the amount of compound remaining. From these data metabolism rates can be calculated. A high degree of automation is achieved through custom software, which is employed for instrument setup, data processing, and results reporting. The assay setup is highly configurable, allowing for any combination of up to six user-selected time points, variable substrate concentration, and microsomes or other biologically active media. The data, based on relative substrate depletion, affords an estimate of metabolic stability through the calculation of half-life (t(1/2)) and intrinsic clearance, which are used to differentiate and rank order drug leads. In general, t(1/2) is the time necessary for the metabolism, following first-order kinetics, of 50% of the initial compound. Intrinsic clearance is the proportionality constant between rate of metabolism of a compound and its concentration at the enzyme site. Described here is the setup of the assay, and data from assay test compounds are presented.
MeSH term(s)	Animals ; Automatic Data Processing ; Automation ; Chromatography, High Pressure Liquid ; Data Interpretation, Statistical ; Drug Evaluation, Preclinical ; Half-Life ; Indicators and Reagents ; Mass Spectrometry ; Mice ; Microsomes, Liver/metabolism ; Pharmaceutical Preparations/metabolism ; Pharmacokinetics ; Rats ; Software ; Solvents ; Spectrophotometry, Ultraviolet
Chemical Substances	Indicators and Reagents ; Pharmaceutical Preparations ; Solvents
Language	English
Publishing date	2008-02
Publishing country	United States
Document type	Journal Article
ISSN	1540-658X
ISSN	1540-658X
DOI	10.1089/adt.2007.103
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Article ; Online: Preclinical characterization of BMS-791325, an allosteric inhibitor of hepatitis C Virus NS5B polymerase.

Lemm, Julie A / Liu, Mengping / Gentles, Robert G / Ding, Min / Voss, Stacey / Pelosi, Lenore A / Wang, Ying-Kai / Rigat, Karen L / Mosure, Kathleen W / Bender, John A / Knipe, Jay O / Colonno, Richard / Meanwell, Nicholas A / Kadow, John F / Santone, Kenneth S / Roberts, Susan B / Gao, Min

Antimicrobial agents and chemotherapy

2014 Volume 58, Issue 6, Page(s) 3485–3495

Abstract: BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) ... ...

Abstract	BMS-791325 is an allosteric inhibitor that binds to thumb site 1 of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. BMS-791325 inhibits recombinant NS5B proteins from HCV genotypes 1, 3, 4, and 5 at 50% inhibitory concentrations (IC50) below 28 nM. In cell culture, BMS-791325 inhibited replication of HCV subgenomic replicons representing genotypes 1a and 1b at 50% effective concentrations (EC50s) of 3 nM and 6 nM, respectively, with similar (3 to 18 nM) values for genotypes 3a, 4a, and 5a. Potency against genotype 6a showed more variability (9 to 125 nM), and activity was weaker against genotype 2 (EC50, 87 to 925 nM). Specificity was demonstrated by the absence of activity (EC50s of >4 μM) against a panel of mammalian viruses, and cytotoxic concentrations (50%) were >3,000-fold above the HCV EC50. Resistance substitutions selected by BMS-791325 in genotype 1 replicons mostly mapped to a single site, NS5B amino acid 495 (P495A/S/L/T). Additive or synergistic activity was observed in combination studies using BMS-791325 with alfa interferon plus ribavirin, inhibitors of NS3 protease or NS5A, and other classes of NS5B inhibitor (palm site 2-binding or nucleoside analogs). Plasma and liver exposures in vivo in several animal species indicated that BMS-791325 has a hepatotropic disposition (liver-to-plasma ratios ranging from 1.6- to 60-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥ 10-fold above the inhibitor EC50s observed with HCV genotype 1 replicons. These findings support the evaluation of BMS-791325 in combination regimens for the treatment of HCV. Phase 3 studies are ongoing.
MeSH term(s)	Allosteric Regulation ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Benzazepines/chemistry ; Benzazepines/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Chlorocebus aethiops ; Dogs ; Drug Resistance, Viral ; Drug Therapy, Combination ; Genotype ; Hepacivirus/drug effects ; Hepacivirus/enzymology ; Humans ; Indoles/chemistry ; Indoles/pharmacology ; Interferon-alpha/pharmacology ; Liver/drug effects ; Liver/metabolism ; Male ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Rats ; Rats, Sprague-Dawley ; Replicon/drug effects ; Ribavirin/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors
Chemical Substances	8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide ; Antiviral Agents ; Benzazepines ; Indoles ; Interferon-alpha ; Viral Nonstructural Proteins ; Ribavirin (49717AWG6K) ; NS-5 protein, hepatitis C virus (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Keywords	covid19
Language	English
Publishing date	2014-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.02495-13
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Article: Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

Zheng, Barbara / D'Andrea, Stanley V / Sun, Li-Qiang / Wang, Alan Xiangdong / Chen, Yan / Hrnciar, Peter / Friborg, Jacques / Falk, Paul / Hernandez, Dennis / Yu, Fei / Sheaffer, Amy K / Knipe, Jay O / Mosure, Kathy / Rajamani, Ramkumar / Good, Andrew C / Kish, Kevin / Tredup, Jeffrey / Klei, Herbert E / Paruchuri, Manjula /

Ng, Alicia / Gao, Qi / Rampulla, Richard A / Mathur, Arvind / Meanwell, Nicholas A / McPhee, Fiona / Scola, Paul M

ACS medicinal chemistry letters

2018 Volume 9, Issue 2, Page(s) 143–148

Abstract: The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure ... ...

Abstract	The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of
Language	English
Publishing date	2018-01-19
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.7b00503
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Article ; Online: Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies.

Yeung, Kap-Sun / Beno, Brett R / Parcella, Kyle / Bender, John A / Grant-Young, Katherine A / Nickel, Andrew / Gunaga, Prashantha / Anjanappa, Prakash / Bora, Rajesh Onkardas / Selvakumar, Kumaravel / Rigat, Karen / Wang, Ying-Kai / Liu, Mengping / Lemm, Julie / Mosure, Kathy / Sheriff, Steven / Wan, Changhong / Witmer, Mark / Kish, Kevin /

Hanumegowda, Umesh / Zhuo, Xiaoliang / Shu, Yue-Zhong / Parker, Dawn / Haskell, Roy / Ng, Alicia / Gao, Qi / Colston, Elizabeth / Raybon, Joseph / Grasela, Dennis M / Santone, Kenneth / Gao, Min / Meanwell, Nicholas A / Sinz, Michael / Soars, Matthew G / Knipe, Jay O / Roberts, Susan B / Kadow, John F

Journal of medicinal chemistry

2017 Volume 60, Issue 10, Page(s) 4369–4385

Abstract: The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site ... ...

Abstract	The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.
MeSH term(s)	Allosteric Regulation/drug effects ; Allosteric Site/drug effects ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Benzofurans/chemistry ; Benzofurans/pharmacokinetics ; Benzofurans/pharmacology ; Dogs ; Drug Discovery ; Haplorhini ; Hepacivirus/drug effects ; Hepatitis C/drug therapy ; Hepatitis C/virology ; Humans ; Male ; Molecular Docking Simulation ; Rats ; Rats, Sprague-Dawley ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Benzofurans ; Viral Nonstructural Proteins ; NS-5 protein, hepatitis C virus (EC 2.7.7.48)
Language	English
Publishing date	2017-05-04
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.7b00328
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Article: HCV NS5A replication complex inhibitors. Part 5: Discovery of potent and pan-genotypic glycinamide cap derivatives

Belema, Makonen / Nguyen, Van N / St. Laurent, Denis R / Lopez, Omar D / Qiu, Yuping / Good, Andrew C / Nower, Peter T / Valera, Lourdes / O’Boyle, Donald R., II / Sun, Jin-Hua / Liu, Mengping / Fridell, Robert A / Lemm, Julie A / Gao, Min / Knipe, Jay O / Meanwell, Nicholas A / Snyder, Lawrence B

Bioorganic & medicinal chemistry letters. 2013 Aug. 1, v. 23, no. 15

2013

Abstract: The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the ... ...

Abstract	The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure–activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described.
Keywords	Hepatitis C virus ; heterocyclic compounds ; structure-activity relationships ; virus replication
Language	English
Dates of publication	2013-0801
Size	p. 4428-4435.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2013.05.040
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