10 results on '"Nowicka-Sans, Beata"'
Search Results
2. 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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3. Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.
- Author
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Lin Z, Cantone J, Lu H, Nowicka-Sans B, Protack T, Yuan T, Yang H, Liu Z, Drexler D, Regueiro-Ren A, Meanwell NA, Cockett M, Krystal M, Lataillade M, and Dicker IB
- Subjects
- Cell Line, HIV-1 genetics, Humans, Microbial Sensitivity Tests, Succinates pharmacology, Triterpenes pharmacology, Virus Assembly drug effects, Anti-HIV Agents pharmacology, Drug Resistance, Viral genetics, HIV-1 drug effects, Virus Replication drug effects, gag Gene Products, Human Immunodeficiency Virus genetics
- Abstract
HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag variants compared to a first generation MI bevirimat (BVM). The underlying mechanistic reasons for the differences in polymorphic coverage were studied using antiviral assays, an LC/MS assay that quantitatively characterizes CA/SP1 cleavage kinetics of virus like particles (VLPs) and a radiolabel binding assay to determine VLP/MI affinities and dissociation kinetics. Antiviral assay data indicates that BVM does not achieve 100% inhibition of certain polymorphs, even at saturating concentrations. This results in the breakthrough of infectious virus (partial antagonism) regardless of BVM concentration. Reduced maximal percent inhibition (MPI) values for BVM correlated with elevated EC50 values, while rates of HIV-1 protease cleavage at CA/SP1 correlated inversely with the ability of BVM to inhibit HIV-1 Gag polymorphic viruses: genotypes with more rapid CA/SP1 cleavage kinetics were less sensitive to BVM. In vitro inhibition of wild type VLP CA/SP1 cleavage by BVM was not maintained at longer cleavage times. BMS-955176 exhibited greatly improved MPI against polymorphic Gag viruses, binds to Gag polymorphs with higher affinity/longer dissociation half-lives and exhibits greater time-independent inhibition of CA/SP1 cleavage compared to BVM. Virological (MPI) and biochemical (CA/SP1 cleavage rates, MI-specific Gag affinities) data were used to create an integrated semi-quantitative model that quantifies CA/SP1 cleavage rates as a function of both MI and Gag polymorph. The model outputs are in accord with in vitro antiviral observations and correlate with observed in vivo MI efficacies. Overall, these findings may be useful to further understand antiviral profiles and clinical responses of MIs at a basic level, potentially facilitating further improvements to MI potency and coverage., Competing Interests: We report the following conflicts of interest: ZLin, JC, HL, BNS, TP, TY, HY, ZLiu, DD, ARR, NAM, MC, MK, ML and ID are employees or former employees of and shareholders in Bristol-Myers Squibb. This does not alter our adherence to all PLOS policies on sharing data and materials.
- Published
- 2016
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4. 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
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5. 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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6. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.
- Author
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Liu Z, Swidorski JJ, Nowicka-Sans B, Terry B, Protack T, Lin Z, Samanta H, Zhang S, Li Z, Parker DD, Rahematpura S, Jenkins S, Beno BR, Krystal M, Meanwell NA, Dicker IB, and Regueiro-Ren A
- Subjects
- Animals, Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Microsomes, Liver virology, Molecular Structure, Rats, Structure-Activity Relationship, Triterpenes chemical synthesis, Triterpenes chemistry, Virus Replication drug effects, Anti-HIV Agents pharmacology, HIV-1 drug effects, HIV-1 growth & development, Triterpenes pharmacology
- Abstract
A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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7. Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068.
- Author
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Zhou N, Nowicka-Sans B, McAuliffe B, Ray N, Eggers B, Fang H, Fan L, Healy M, Langley DR, Hwang C, Lataillade M, Hanna GJ, and Krystal M
- Subjects
- Amino Acid Substitution, Anti-HIV Agents therapeutic use, HIV Infections drug therapy, HIV Infections virology, HIV-1 genetics, Humans, Molecular Sequence Data, Organophosphates therapeutic use, Piperazines therapeutic use, Prodrugs therapeutic use, Reverse Genetics, Sequence Analysis, DNA, Triazoles therapeutic use, Anti-HIV Agents pharmacology, Drug Resistance, Viral, HIV Envelope Protein gp120 genetics, HIV-1 drug effects, Organophosphates pharmacology, Piperazines pharmacology, Prodrugs pharmacology, Triazoles pharmacology
- Abstract
Objectives: In an 8 day monotherapy study of subjects infected with HIV-1 (subtype B) (NCT01009814), BMS-626529 (an attachment inhibitor that binds to HIV-1 envelope glycoprotein gp120), administered as the prodrug BMS-663068, produced substantial declines in plasma HIV-1 RNA. However, large variability in susceptibility to BMS-626529 was noted and virus with low susceptibility was less likely to be suppressed by BMS-663068 administration. The current analysis sought to investigate the genotypic correlates of susceptibility to BMS-626529., Methods: In vitro selection experiments, evaluation of clinical samples of subtype B from the monotherapy study and evaluation of intrinsically resistant subtype AE viruses were conducted. Reverse genetics was used to identify key substitutions in envelope clones responsible for reduced susceptibility., Results: An M426L or S375M change were the major substitutions associated with reductions in susceptibility to BMS-626529 in baseline samples of subtype B viruses from the monotherapy study, with M434I and M475I contributing to a lesser extent. Class resistance in subtype AE viruses was mapped to 375H and 475I substitutions, found in the vast majority of these viruses. Analysis of multiple envelope clones from infected subjects showed higher intrasubject variability in susceptibility to BMS-626529 compared with other classes of entry inhibitors., Conclusions: These data define key genotypic substitutions in HIV-1 gp120 that could confer phenotypic resistance to BMS-626529.
- Published
- 2014
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8. In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068.
- Author
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Nowicka-Sans B, Gong YF, McAuliffe B, Dicker I, Ho HT, Zhou N, Eggers B, Lin PF, Ray N, Wind-Rotolo M, Zhu L, Majumdar A, Stock D, Lataillade M, Hanna GJ, Matiskella JD, Ueda Y, Wang T, Kadow JF, Meanwell NA, and Krystal M
- Subjects
- Anti-HIV Agents chemistry, Cells, Cultured, HCT116 Cells, HIV drug effects, HIV metabolism, HIV Envelope Protein gp120 metabolism, HeLa Cells, Hep G2 Cells, Humans, Anti-HIV Agents pharmacology
- Abstract
BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4(+) T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1, in vitro activities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC(50)) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log(10), with half-maximal effective concentration values in the low pM range against the most susceptible viruses. The in vitro antiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.
- Published
- 2012
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9. Inhibitors of human immunodeficiency virus type 1 (HIV-1) attachment. 5. An evolution from indole to azaindoles leading to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043), a drug candidate that demonstrates antiviral activity in HIV-1-infected subjects.
- Author
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Wang T, Yin Z, Zhang Z, Bender JA, Yang Z, Johnson G, Yang Z, Zadjura LM, D'Arienzo CJ, DiGiugno Parker D, Gesenberg C, Yamanaka GA, Gong YF, Ho HT, Fang H, Zhou N, McAuliffe BV, Eggers BJ, Fan L, Nowicka-Sans B, Dicker IB, Gao Q, Colonno RJ, Lin PF, Meanwell NA, and Kadow JF
- Subjects
- Animals, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacokinetics, Anti-HIV Agents therapeutic use, Cell Line, Drug Discovery, Humans, Models, Molecular, Molecular Conformation, Piperazines chemistry, Piperazines pharmacokinetics, Piperazines therapeutic use, Pyruvic Acid, Rats, Reproducibility of Results, Anti-HIV Agents pharmacology, HIV Infections drug therapy, HIV-1 drug effects, HIV-1 physiology, Indoles chemistry, Piperazines pharmacology, Virus Attachment drug effects
- Abstract
Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.
- Published
- 2009
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10. Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events.
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Ho HT, Fan L, Nowicka-Sans B, McAuliffe B, Li CB, Yamanaka G, Zhou N, Fang H, Dicker I, Dalterio R, Gong YF, Wang T, Yin Z, Ueda Y, Matiskella J, Kadow J, Clapham P, Robinson J, Colonno R, and Lin PF
- Subjects
- HIV Envelope Protein gp120 drug effects, HeLa Cells, Humans, Indoles, Piperazines pharmacology, Protein Conformation, Pyruvic Acid, Virion drug effects, Anti-HIV Agents pharmacology, CD4 Antigens metabolism, HIV Envelope Protein gp120 chemistry, HIV-1 drug effects
- Abstract
BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.
- Published
- 2006
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