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Dive into the research topics where Brian Lee Venables is active.

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Featured researches published by Brian Lee Venables.


Antimicrobial Agents and Chemotherapy | 2004

Orally Active Fusion Inhibitor of Respiratory Syncytial Virus

Christopher Cianci; Kuo-Long Yu; Keith D. Combrink; Ny Sin; Bradley C. Pearce; Alan X. Wang; Rita L. Civiello; Stacey Voss; Guangxiang Luo; Kathy Kadow; Eugene V. Genovesi; Brian Lee Venables; Hatice Belgin Gulgeze; Ashok K. Trehan; Jennifer James; Lucinda Lamb; Ivette Medina; Julia Roach; Zheng Yang; Lisa Zadjura; Richard J. Colonno; Junius M. Clark; Nicholas A. Meanwell; Mark Krystal

ABSTRACT BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation. After isolation of resistant viruses, resistance was mapped to a series of single amino acid mutations in the F1 subunit of the fusion protein. Upon oral administration, BMS-433771 was able to reduce viral titers in the lungs of mice infected with RSV. This new class of orally active RSV fusion inhibitors offers potential for clinical development.


Journal of Medicinal Chemistry | 2014

The Discovery of Asunaprevir (BMS-650032), An Orally Efficacious NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

Paul Michael Scola; Li-Qiang Sun; Alan Xiangdong Wang; Jie Chen; Ny Sin; Brian Lee Venables; Sing-Yuen Sit; Yan Chen; Anthony J. Cocuzza; Donna M. Bilder; Stanley V. D’Andrea; Barbara Zheng; Piyasena Hewawasam; Yong Tu; Jacques Friborg; Paul Falk; Dennis Hernandez; Steven Levine; Chaoqun Chen; Fei Yu; Amy K. Sheaffer; Guangzhi Zhai; Diana Barry; Jay O. Knipe; Yong-Hae Han; Richard Schartman; Maria Donoso; Kathy Mosure; Michael Sinz; Tatyana Zvyaga

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).


Bioorganic & Medicinal Chemistry Letters | 2002

Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease

David Sperandio; Anthony R. Gangloff; Joane Litvak; Richard Goldsmith; Jason M. Hataye; Vivian R. Wang; Emma J. Shelton; Kyle Elrod; James W. Janc; James M. Clark; Ken Rice; Steve Weinheimer; Kap-Sun Yeung; Nicholas A. Meanwell; Dennis Hernandez; Andrew J. Staab; Brian Lee Venables; Jeffrey R. Spencer

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.


Antimicrobial Agents and Chemotherapy | 2016

Identification and Characterization of BMS-955176, a Second-Generation HIV-1 Maturation Inhibitor with Improved Potency, Antiviral Spectrum, and Gag Polymorphic Coverage

Beata Nowicka-Sans; Tricia Protack; Zeyu Lin; Zhufang Li; Sharon Zhang; Yongnian Sun; Himadri Samanta; Brian Terry; Zheng Liu; Yan Chen; Ny Sin; Sing-Yuen Sit; Jacob Swidorski; Jie Chen; Brian Lee Venables; Matthew D. Healy; Nicholas A. Meanwell; Mark Cockett; Umesh Hanumegowda; Alicia Regueiro-Ren; Mark Krystal; Ira B. Dicker

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.


Bioorganic & Medicinal Chemistry Letters | 2009

Respiratory syncytial virus fusion inhibitors. Part 7: Structure–activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo

Ny Sin; Brian Lee Venables; Keith D. Combrink; H. Belgin Gulgeze; Kuo-Long Yu; Rita L. Civiello; Jan Willem Thuring; X. Alan Wang; Zheng Yang; Lisa Zadjura; Anthony Marino; Kathleen F. Kadow; Christopher Cianci; Junius Clarke; Eugene V. Genovesi; Ivette Medina; Lucinda Lamb; Mark Krystal; Nicholas A. Meanwell

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.


ACS Medicinal Chemistry Letters | 2016

Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity

Alicia Regueiro-Ren; Zheng Liu; Yan Chen; Ny Sin; Sing-Yuen Sit; Jacob Swidorski; Jie Chen; Brian Lee Venables; Juliang Zhu; Beata Nowicka-Sans; Tricia Protack; Zeyu Lin; Brian Terry; Himadri Samanta; Sharon Zhang; Zhufang Li; Brett R. Beno; Xiaohua S. Huang; Sandhya Rahematpura; Dawn D. Parker; Roy Haskell; Susan R. Jenkins; Kenneth S. Santone; Mark Cockett; Mark Krystal; Nicholas A. Meanwell; Umesh Hanumegowda; Ira B. Dicker

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.


Bioorganic & Medicinal Chemistry Letters | 2016

Inhibitors of HIV-1 maturation: Development of structure–activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids

Jacob Swidorski; Zheng Liu; Sing-Yuen Sit; Jie Chen; Yan Chen; Ny Sin; Brian Lee Venables; Dawn D. Parker; Beata Nowicka-Sans; Brian Terry; Tricia Protack; Sandhya Rahematpura; Umesh Hanumegowda; Susan Jenkins; Mark Krystal; Ira B. Dicker; Nicholas A. Meanwell; Alicia Regueiro-Ren

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.


Journal of Medicinal Chemistry | 2016

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

Li-Qiang Sun; Eric Mull; Barbara Zheng; Stanley V. D’Andrea; Qian Zhao; Alan Xiangdong Wang; Ny Sin; Brian Lee Venables; Sing-Yuen Sit; Yan Chen; Jie Chen; Anthony J. Cocuzza; Donna M. Bilder; Arvind Mathur; Richard Rampulla; Bang-Chi Chen; Theerthagiri Palani; Sivakumar Ganesan; Pirama Nayagam Arunachalam; Paul Falk; Steven Levine; Chaoqun Chen; Jacques Friborg; Fei Yu; Dennis Hernandez; Amy K. Sheaffer; Jay O. Knipe; Yong-Hae Han; Richard Schartman; Maria Donoso

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).


Magnetic Resonance in Chemistry | 2010

15N chemical shifts of a series of isatin oxime ethers and their corresponding nitrone isomers.

Xiaohong Liu; Xiaohua Stella Huang; Ny Sin; Brian Lee Venables; Vikram Roongta

In this article, we describe the characteristic 15N 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 15N 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 15N 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 15N NMR chemical shifts serve as the basis for a discussion about how to distinguish both regioisomers derived from the oximes alkylation. Copyright


Bioorganic & Medicinal Chemistry Letters | 2018

The Design, Synthesis and Structure-Activity Relationships Associated with C28 Amine-Based Betulinic Acid Derivatives as Inhibitors of HIV-1 Maturation

Yan Chen; Sing-Yuen Sit; Jie Chen; Jacob Swidorski; Zheng Liu; Ny Sin; Brian Lee Venables; Dawn D. Parker; Beata Nowicka-Sans; Zeyu Lin; Zhufang Li; Brian Terry; Tricia Protack; Sandhya Rahematpura; Umesh Hanumegowda; Susan R. Jenkins; Mark Krystal; Ira D. Dicker; Nicholas A. Meanwell; Alicia Regueiro-Ren

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 EC50 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.

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Ny Sin

Bristol-Myers Squibb

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Jie Chen

Bristol-Myers Squibb

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Yan Chen

Bristol-Myers Squibb

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