15 results on '"Venables BL"'
Search Results
2. The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation.
- Author
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Regueiro-Ren A, Sit SY, Chen Y, Chen J, Swidorski JJ, Liu Z, Venables BL, Sin N, Hartz RA, Protack T, Lin Z, Zhang S, Li Z, Wu DR, Li P, Kempson J, Hou X, Gupta A, Rampulla R, Mathur A, Park H, Sarjeant A, Benitex Y, Rahematpura S, Parker D, Phillips T, Haskell R, Jenkins S, Santone KS, Cockett M, Hanumegowda U, Dicker I, Meanwell NA, and Krystal M
- Subjects
- Humans, Benzoic Acid chemistry, Carbon, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Anti-HIV Agents therapeutic use, HIV-1, Triterpenes chemistry, Triterpenes pharmacology, Triterpenes therapeutic use
- Abstract
GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para -substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH
2 F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.- Published
- 2022
- Full Text
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3. Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176).
- Author
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Regueiro-Ren A, Swidorski JJ, Liu Z, Chen Y, Sin N, Sit SY, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Easter J, Beno BR, Arora V, Huang XS, Rahematpura S, Parker DD, Haskell R, Santone KS, Cockett MI, Krystal M, Meanwell NA, Jenkins S, Hanumegowda U, and Dicker IB
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Administration, Oral, Animals, Anti-HIV Agents pharmacokinetics, Benzoic Acid chemistry, Biological Availability, Chemistry Techniques, Synthetic, Chrysenes pharmacology, Dogs, Drug Design, Drug Stability, HIV-1 drug effects, HIV-1 genetics, Humans, Macaca fascicularis, Male, Mice, Inbred Strains, Mice, Knockout, Microsomes, Liver drug effects, Morpholines pharmacology, Polymorphism, Genetic, Rats, Sprague-Dawley, Triterpenes pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Chrysenes chemistry, Morpholines chemistry, Structure-Activity Relationship, Triterpenes chemistry
- Abstract
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC
50 <15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.- Published
- 2018
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4. P3-P4 ureas and reverse carbamates as potent HCV NS3 protease inhibitors: Effective transposition of the P4 hydrogen bond donor.
- Author
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Venables BL, Sin N, Wang AX, Sun LQ, Tu Y, Hernandez D, Sheaffer A, Lee M, Dunaj C, Zhai G, Barry D, Friborg J, Yu F, Knipe J, Sandquist J, Falk P, Parker D, Good AC, Rajamani R, McPhee F, Meanwell NA, and Scola PM
- Subjects
- Animals, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Binding Sites, Half-Life, Hepacivirus drug effects, Hepacivirus enzymology, Humans, Hydrogen Bonding, Liver metabolism, Molecular Dynamics Simulation, Protease Inhibitors pharmacokinetics, Protease Inhibitors pharmacology, Protein Structure, Tertiary, Rats, Structure-Activity Relationship, Viral Nonstructural Proteins metabolism, Antiviral Agents chemistry, Carbamates chemistry, Protease Inhibitors chemistry, Urea chemistry, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues were less than optimal. In an effort to overcome the PK shortcomings, modifications to the P3-P4 junction were made. This included a strategy in which one of the two urea N-H groups was either N-methylated or replaced with an oxygen atom. The former approach provided a series of regioisomeric N-methylated ureas while the latter gave rise to P4 reverse carbamates, both of which retained potent NS3 inhibitory properties while relying upon an alternative H-bond donor topology. Details of the SARs and PK profiles of these analogues are provided., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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5. The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation.
- Author
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Chen Y, Sit SY, Chen J, Swidorski JJ, Liu Z, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Lin Z, Li Z, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker ID, Meanwell NA, and Regueiro-Ren A
- Subjects
- Amines chemistry, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Molecular Conformation, Pentacyclic Triterpenes, Structure-Activity Relationship, Triterpenes chemical synthesis, Triterpenes chemistry, Betulinic Acid, Amines pharmacology, Anti-HIV Agents pharmacology, Drug Design, HIV-1 drug effects, Triterpenes pharmacology
- Abstract
The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC
50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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6. Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.
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Sun LQ, Mull E, Zheng B, D'Andrea S, Zhao Q, Wang AX, Sin N, Venables BL, Sit SY, Chen Y, Chen J, Cocuzza A, Bilder DM, Mathur A, Rampulla R, Chen BC, Palani T, Ganesan S, Arunachalam PN, Falk P, Levine S, Chen C, Friborg J, Yu F, Hernandez D, Sheaffer AK, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Ng A, Mueller L, Grasela DM, Adams S, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Wang YK, Fang H, Cockett MI, Meanwell NA, McPhee F, and Scola PM
- Subjects
- Animals, Antiviral Agents administration & dosage, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Dogs, Drug Administration Schedule, Drug Resistance, Viral, Hepacivirus genetics, Macaca fascicularis, Male, Models, Molecular, Oligopeptides administration & dosage, Oligopeptides pharmacokinetics, Oligopeptides pharmacology, Rabbits, Rats, Sprague-Dawley, Replicon, Stereoisomerism, Structure-Activity Relationship, Sulfonamides administration & dosage, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Sulfonamides therapeutic use, Antiviral Agents chemistry, Hepacivirus drug effects, Isoquinolines therapeutic use, Oligopeptides chemistry, Sulfonamides chemistry, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
- Published
- 2016
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7. Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage.
- Author
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Nowicka-Sans B, Protack T, Lin Z, Li Z, Zhang S, Sun Y, Samanta H, Terry B, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Healy M, Meanwell NA, Cockett M, Hanumegowda U, Regueiro-Ren A, Krystal M, and Dicker IB
- Subjects
- Drug Resistance, Viral genetics, HIV-1 metabolism, Humans, Succinates pharmacology, Triterpenes pharmacology, Virus Replication drug effects, Anti-HIV Agents pharmacology, HIV-1 drug effects, gag Gene Products, Human Immunodeficiency Virus antagonists & inhibitors
- Abstract
BMS-955176 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor (MI). A first-generation MI, bevirimat, showed clinical efficacy in early-phase studies, but ∼50% of subjects had viruses with reduced susceptibility associated with naturally occurring polymorphisms in Gag near the site of MI action. MI potency was optimized using a panel of engineered reporter viruses containing site-directed polymorphic changes in Gag that reduce susceptibility to bevirimat (including V362I, V370A/M/Δ, and T371A/Δ), leading incrementally to the identification of BMS-955176. BMS-955176 exhibits potent activity (50% effective concentration [EC50], 3.9 ± 3.4 nM [mean ± standard deviation]) toward a library (n = 87) of gag/pr recombinant viruses representing 96.5% of subtype B polymorphic Gag diversity near the CA/SP1 cleavage site. BMS-955176 exhibited a median EC50 of 21 nM toward a library of subtype B clinical isolates assayed in peripheral blood mononuclear cells (PBMCs). Potent activity was maintained against a panel of reverse transcriptase, protease, and integrase inhibitor-resistant viruses, with EC50s similar to those for the wild-type virus. A 5.4-fold reduction in EC50 occurred in the presence of 40% human serum plus 27 mg/ml of human serum albumin (HSA), which corresponded well to an in vitro measurement of 86% human serum binding. Time-of-addition and pseudotype reporter virus studies confirm a mechanism of action for the compound that occurs late in the virus replication cycle. BMS-955176 inhibits HIV-1 protease cleavage at the CA/SP1 junction within Gag in virus-like particles (VLPs) and in HIV-1-infected cells, and it binds reversibly and with high affinity to assembled Gag in purified HIV-1 VLPs. Finally, in vitro combination studies showed no antagonistic interactions with representative antiretrovirals (ARVs) of other mechanistic classes. In conclusion, BMS-955176 is a second-generation MI with potent in vitro anti-HIV-1 activity and a greatly improved preclinical profile compared to that of bevirimat., (Copyright © 2016 Nowicka-Sans et al.)
- Published
- 2016
- Full Text
- View/download PDF
8. Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity.
- Author
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Regueiro-Ren A, Liu Z, Chen Y, Sin N, Sit SY, Swidorski JJ, Chen J, Venables BL, Zhu J, Nowicka-Sans B, Protack T, Lin Z, Terry B, Samanta H, Zhang S, Li Z, Beno BR, Huang XS, Rahematpura S, Parker DD, Haskell R, Jenkins S, Santone KS, Cockett MI, Krystal M, Meanwell NA, Hanumegowda U, and Dicker IB
- Abstract
HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.
- Published
- 2016
- Full Text
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9. Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids.
- Author
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Swidorski JJ, Liu Z, Sit SY, Chen J, Chen Y, Sin N, Venables BL, Parker DD, Nowicka-Sans B, Terry BJ, Protack T, Rahematpura S, Hanumegowda U, Jenkins S, Krystal M, Dicker IB, Meanwell NA, and Regueiro-Ren A
- Subjects
- Administration, Oral, Amides administration & dosage, Amides chemistry, Animals, Anti-HIV Agents administration & dosage, Benzoates administration & dosage, Benzoates chemistry, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Molecular Structure, Rats, Structure-Activity Relationship, Triterpenes administration & dosage, Triterpenes chemistry, Amides pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Benzoates pharmacology, HIV drug effects, HIV growth & development, Triterpenes pharmacology
- Abstract
We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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- View/download PDF
10. Discovery and early clinical evaluation of BMS-605339, a potent and orally efficacious tripeptidic acylsulfonamide NS3 protease inhibitor for the treatment of hepatitis C virus infection.
- Author
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Scola PM, Wang AX, Good AC, Sun LQ, Combrink KD, Campbell JA, Chen J, Tu Y, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea S, Zheng B, Hewawasam P, Ding M, Thuring J, Li J, Hernandez D, Yu F, Falk P, Zhai G, Sheaffer AK, Chen C, Lee MS, Barry D, Knipe JO, Li W, Han YH, Jenkins S, Gesenberg C, Gao Q, Sinz MW, Santone KS, Zvyaga T, Rajamani R, Klei HE, Colonno RJ, Grasela DM, Hughes E, Chien C, Adams S, Levesque PC, Li D, Zhu J, Meanwell NA, and McPhee F
- Subjects
- Animals, Crystallography, X-Ray, Dogs, Drug Evaluation, Preclinical, Humans, Isoquinolines chemistry, Models, Molecular, Protease Inhibitors chemistry, Sulfonamides chemistry, Antiviral Agents therapeutic use, Drug Discovery, Hepatitis C drug therapy, Isoquinolines therapeutic use, Protease Inhibitors therapeutic use, Sulfonamides therapeutic use, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
- Published
- 2014
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11. The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.
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Scola PM, Sun LQ, Wang AX, Chen J, Sin N, Venables BL, Sit SY, Chen Y, Cocuzza A, Bilder DM, D'Andrea SV, Zheng B, Hewawasam P, Tu Y, Friborg J, Falk P, Hernandez D, Levine S, Chen C, Yu F, Sheaffer AK, Zhai G, Barry D, Knipe JO, Han YH, Schartman R, Donoso M, Mosure K, Sinz MW, Zvyaga T, Good AC, Rajamani R, Kish K, Tredup J, Klei HE, Gao Q, Mueller L, Colonno RJ, Grasela DM, Adams SP, Loy J, Levesque PC, Sun H, Shi H, Sun L, Warner W, Li D, Zhu J, Meanwell NA, and McPhee F
- Subjects
- Animals, Antiviral Agents blood, Antiviral Agents chemistry, Dogs, Humans, Isoquinolines blood, Isoquinolines chemistry, Models, Molecular, Protease Inhibitors blood, Protease Inhibitors chemistry, Rabbits, Rats, Sulfonamides blood, Sulfonamides chemistry, Antiviral Agents therapeutic use, Hepatitis C drug therapy, Isoquinolines therapeutic use, Protease Inhibitors therapeutic use, Sulfonamides therapeutic use, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
- Published
- 2014
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12. 15N chemical shifts of a series of isatin oxime ethers and their corresponding nitrone isomers.
- Author
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Liu X, Huang XS, Sin N, Venables BL, and Roongta V
- Subjects
- Alkylation, Electrons, Ethers chemical synthesis, Isatin analogs & derivatives, Isatin chemical synthesis, Magnetic Resonance Spectroscopy standards, Molecular Structure, Nitrogen Isotopes, Nitrogen Oxides chemical synthesis, Oximes chemical synthesis, Reference Standards, Stereoisomerism, Ethers chemistry, Isatin chemistry, Nitrogen Oxides chemistry, Oximes chemistry
- Abstract
In this article, we describe the characteristic (15)N chemical shifts of isatin oxime ethers and their isomer nitrone. These oxime ethers and nitrones are the alkylation reaction products of isatin oximes. In our study, the (15)N chemical shifts observed in these oxime ethers were in the 402-408 (or 22-28) ppm range, although those for their corresponding nitrone series were in the 280-320 (or -100 to -60) ppm range. This remarkable difference in (15)N NMR chemical shift values could potentially be used to determine the O- versus N-alkylation of oximes, even when only one isomer is available. In this paper, the differences in (15)N NMR chemical shifts serve as the basis for a discussion about how to distinguish both regioisomers derived from the oximes alkylation., (2010 John Wiley & Sons, Ltd.)
- Published
- 2010
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13. Respiratory syncytial virus fusion inhibitors. Part 7: structure-activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo.
- Author
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Sin N, Venables BL, Combrink KD, Gulgeze HB, Yu KL, Civiello RL, Thuring J, Wang XA, Yang Z, Zadjura L, Marino A, Kadow KF, Cianci CW, Clarke J, Genovesi EV, Medina I, Lamb L, Krystal M, and Meanwell NA
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Benzimidazoles chemical synthesis, Benzimidazoles chemistry, Benzimidazoles pharmacokinetics, Caco-2 Cells, Cell Line, Tumor, Humans, Mice, Mice, Inbred BALB C, Microsomes, Liver metabolism, Rats, Structure-Activity Relationship, Antiviral Agents chemistry, Isatin chemistry, Oximes chemistry, Respiratory Syncytial Viruses drug effects
- Abstract
A series of bezimidazole-isatin oximes were prepared and profiled as inhibitors of respiratory syncytial virus (RSV) replication in cell culture. Structure-activity relationship studies were directed toward optimization of antiviral activity, cell permeability and metabolic stability in human liver micorosomes (HLM). Parallel combinatorial synthetic chemistry was employed to functionalize isatin oximes via O-alkylation which quickly identified a subset of small, lipophilic substituents that established good potency for the series. Further optimization of the isatin oxime derivatives focused on introduction of nitrogen atoms to the isatin phenyl ring to provide a series of aza-isatin oximes with significantly improved PK properties. Several aza-isatin oximes analogs displayed targeted metabolic stability in HLM and permeability across a confluent monolayer of CaCo-2 cells. These studies identified several compounds, including 18i, 18j and 18n that demonstrated antiviral activity in the BALB/c mouse model of RSV infection following oral dosing.
- Published
- 2009
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14. Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability.
- Author
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Yu KL, Sin N, Civiello RL, Wang XA, Combrink KD, Gulgeze HB, Venables BL, Wright JJ, Dalterio RA, Zadjura L, Marino A, Dando S, D'Arienzo C, Kadow KF, Cianci CW, Li Z, Clarke J, Genovesi EV, Medina I, Lamb L, Colonno RJ, Yang Z, Krystal M, and Meanwell NA
- Subjects
- Animals, Antiviral Agents pharmacokinetics, Benzimidazoles pharmacokinetics, Biological Availability, Caco-2 Cells, Chemical Phenomena, Chemistry, Physical, Cytopathogenic Effect, Viral drug effects, Dogs, Half-Life, Humans, In Vitro Techniques, Macaca fascicularis, Mice, Mice, Inbred BALB C, Microsomes, Liver drug effects, Rats, Respiratory Syncytial Virus Infections drug therapy, Respiratory Syncytial Virus Infections virology, Sigmodontinae, Structure-Activity Relationship, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Benzimidazoles chemical synthesis, Benzimidazoles pharmacology, Respiratory Syncytial Virus, Human drug effects
- Abstract
A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration.
- Published
- 2007
- Full Text
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15. Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease.
- Author
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Sperandio D, Gangloff AR, Litvak J, Goldsmith R, Hataye JM, Wang VR, Shelton EJ, Elrod K, Janc JW, Clark JM, Rice K, Weinheimer S, Yeung KS, Meanwell NA, Hernandez D, Staab AJ, Venables BL, and Spencer JR
- Subjects
- Edetic Acid, Indicators and Reagents, Peptides chemical synthesis, Peptides pharmacology, RNA, Viral chemistry, RNA, Viral genetics, Structure-Activity Relationship, Zinc pharmacology, Benzimidazoles chemical synthesis, Benzimidazoles pharmacology, Hepacivirus enzymology, Serine Proteinase Inhibitors chemical synthesis, Serine Proteinase Inhibitors pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
- Published
- 2002
- Full Text
- View/download PDF
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