1392312-45-6|GSK3532795|GSK3532795|-范德生物科技公司

GSK3532795

NMR下载 COA and HPLC MSDS下载
names：
GSK3532795
CAS号：
1392312-45-6
MDL Number：
MF(分子式)： C42H62N2O4S MW(分子量)： 691.02
EINECS: Reaxys Number:
Pubchem ID:60152109 Brand:BIOFOUNT

GSK3532795(1392312-45-6,BMS55176)是一种有效的、可口服、第二代HIV-1成熟的抑制剂，对 HIV-1 WT，HIV-1 WT(人血清)，HIV-1 V370A 和 HIV-1 ΔV370 的EC50值分别是 1.9，10.2，2.7 和 13 nM。

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中文别名	GSK3532795(1392312-45-6);BMS-955176;BMS-955176 (GSK-3532795;GSK3532795;GSK3532795;
英文别名	GSK3532795(1392312-45-6);BMS-955176;BMS-955176 (GSK-3532795;GSK3532795;GSK3532795;BMS-955176(free base);benzoic acid, 4-(17-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-28-norlupa-2,20(29)-dien-3-yl)-;BMS-955176;
CAS号	1392312-45-6
SMILES	CC1(C)C(C2=CC=C(C(O)=O)C=C2)=CC[C@@]3(C)[C@@]1([H])CC[C@]4(C)[C@]3([H])CC[C@@]5([H])[C@@]4(C)CC[C@]6(NCCN7CCS(CC7)(=O)=O)[C@]5([H])[C@H](C(C)=C)CC6
Inchi	No data available
InchiKey	No data available
分子式 Formula	C42H62N2O4S
分子量 Molecular Weight	691.02
闪点 FP	425.9±32.9°摄氏度
熔点 Melting point	No data available
沸点 Boiling point	760毫米汞柱时为780.7±60.0°C
Polarizability极化度
密度 Density	1.2±0.1克/厘米3
蒸汽压 Vapor Pressure	25°C时0.0±2.8 mmHg
溶解度Solubility
性状	Solid
储藏条件 Storage conditions	请根据产品建议的存储条件进行存储,Please store the product under the recommended condition sin the description.

GSK3532795(1392312-45-6,BMS55176)实验注意事项：
1.实验前需戴好防护眼镜，穿戴防护服和口罩，佩戴手套，避免与皮肤接触。
2.实验过程中如遇到有毒或者刺激性物质及有害物质产生，必要时实验操作需要手套箱内完成以免对实验人员造成伤害
3.实验后产生的废弃物需分类存储，并交于专业生物废气物处理公司处理，以免造成环境污染Experimental considerations:
1. Wear protective glasses, protective clothing and masks, gloves, and avoid contact with the skin during the experiment.
2. The waste generated after the experiment needs to be stored separately, and handed over to a professional biological waste gas treatment company to avoid environmental pollution.

Tags:GSK3532795试剂,GSK3532795杂质,GSK3532795中间体,GSK3532795密度,GSK3532795溶解度,GSK3532795旋光度,GSK3532795结构式,GSK3532795闪点,GSK3532795购买,

产品说明	GSK3532795(1392312-45-6,BMS55176)是一种有效的、可口服、第二代HIV-1成熟的抑制剂。
Introduction	GSK3532795(1392312-45-6,BMS55176) is a potent, orally active, secondenerationHIVmaturation inhibitor, withEC50s of 1.9, 10.2, 2.7 and 13 nM for HIV WT, HIV WT(human serum),
Application1	HIV V370A, and HIV ΔV370, respectively.
Application2	(1392312-45-6)GSK3532795 是一种有效的、可口服、第二代HIV-1成熟的抑制剂，对 HIV-1 WT，HIV-1 WT(人血清)，HIV-1 V370A 和 HIV-1 ΔV370 的EC50值分别是 1.9，10.2，2.7 和 13 nM
Application3

GSK3532795(1392312-45-6,BMS55176)药理学：

(1392312-45-6)GSK3532795 是一种有效的、可口服、第二代HIV-1成熟的抑制剂，对 HIV-1 WT，HIV-1 WT(人血清)，HIV-1 V370A 和 HIV-1 ΔV370 的EC50值分别是 1.9，10.2，2.7 和 13 nM

警示图
危险性	warning
危险性警示	Not available
安全声明	H303吞入可能有害+H313皮肤接触可能有害+H2413吸入可能对身体有害
安全防护	P264处理后彻底清洗+P280戴防护手套/穿防护服/戴防护眼罩/戴防护面具+P305如果进入眼睛+P351用水小心冲洗几分钟+P338取出隐形眼镜（如果有）并且易于操作,继续冲洗+P337如果眼睛刺激持续+P2393获得医疗建议/护理
备注	实验过程中防止吸入、食入，做好安全防护

A Phase 2b Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy and Dose-response of BMS-955176, Given on a Backbone of Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 I

Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the Pharmacodynamics, Safety and Pharmacokinetics of BMS-955176 (Double-Blinded) and BMS-955176 with Atazanavir +/- Ritonavir (Open-Labe

Study to Evaluate a HIV Drug for the Treatment of HIV Infection Phase 2 Completed 2019-11-25

Dose-finding Study of BMS-955176 to Treat HIV-1 Infected Treatment-naive Adults Phase 2 Terminated 2018-09-19

Strategy-confirming Study of BMS-955176 to Treat HIV-1 Infected Treatment-experienced Adults Phase 2 Terminated 2018-08-20

GSK3532795(1392312-45-6,BMS55176)参考文献：

1、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 1, Tricia Protack 1, Zeyu Lin 1, Zhufang Li 1, Sharon Zhang 1, Yongnian Sun 1, Himadri Samanta 1, Brian Terry 1, Zheng Liu 2, Yan Chen 2, Ny Sin 2, Sing-Yuen Sit 2, Jacob J Swidorski 2, Jie Chen 2, Brian L Venables 2, Matthew Healy 3, Nicholas A Meanwell 2, Mark Cockett 1, Umesh Hanumegowda 4, Alicia Regueiro-Ren 2, Mark Krystal 1, 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.

2、Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity
Alicia Regueiro-Ren 1, Zheng Liu 1, Yan Chen 1, Ny Sin 1, Sing-Yuen Sit 1, Jacob J Swidorski 1, Jie Chen 1, Brian L Venables 1, Juliang Zhu 1, Beata Nowicka-Sans 1, Tricia Protack 1, Zeyu Lin 1, Brian Terry 1, Himadri Samanta 1, Sharon Zhang 1, Zhufang Li 1, Brett R Beno 1, Xiaohua S Huang 1, Sandhya Rahematpura 1, Dawn D Parker 1, Roy Haskell 1, Susan Jenkins 1, Kenneth S Santone 1, Mark I Cockett 1, Mark Krystal 1, Nicholas A Meanwell 1, Umesh Hanumegowda 1, Ira B Dicker

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.

3、Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors
Zeyu Lin 1, Joseph Cantone 2, Hao Lu 2, Beata Nowicka-Sans 1, Tricia Protack 1, Tian Yuan 3, Hong Yang 3, Zheng Liu 4, Dieter Drexler 2, Alicia Regueiro-Ren 4, Nicholas A Meanwell 4, Mark Cockett 1, Mark Krystal 1, Max Lataillade 5, Ira B Dicker

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.

4、Second Generation Inhibitors of HIV-1 Maturation
Alicia Regueiro-Ren 1, Ira B Dicker 2, Umesh Hanumegowda 2, Nicholas A Meanwell

Abstract The strategy and tactics subtending the discovery and development of the second generation HIV-1 maturation inhibitor GSK-3532795/BMS-955176, a compound that exhibits a broader spectrum of antiviral effect in vitro and in clinical studies than the prototypical maturation inhibitor bevirimat, are described.

5、Antiviral Activity, Safety, and Exposure-Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002)
Carey Hwang 1, Dirk Schürmann 2 3, Christian Sobotha 2, Marta Boffito 4, Heather Sevinsky 1, Neelanjana Ray 1, Palanikumar Ravindran 1, Hong Xiao 1, Christian Keicher 2, Andreas Hüser 2, Mark Krystal 5, Ira B Dicker 5, Dennis Grasela 1, Max Lataillade

Abstract Background: GSK3532795 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage between capsid protein p24 and spacer protein-1, producing immature, noninfectious virions. Methods: This was a phase 2a, randomized, dose-ranging multipart trial. In part A, subtype B-infected subjects received 5-120 mg GSK3532795 (or placebo) once daily for 10 days. In part B, subtype B-infected subjects received 40 mg or 80 mg GSK3532795 once daily with atazanavir (ATV) with or without (±) ritonavir (RTV) or standard of care (SOC) (tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and ATV/RTV 300 mg/100 mg) for 28 days. In part C, subtype C-infected subjects received 40 mg or 120 mg GSK3532795 once daily (or placebo) for 10 days. Endpoints included change in HIV-1 RNA from baseline on day 11 (parts A/C) or day 29 (part B). Results: A >1 log10 median decline in HIV-1 RNA was achieved by day 11 in parts A and C and day 29 in part B at GSK3532795 doses ≥40 mg; part B subjects receiving GSK3532795 and ATV ± RTV achieved similar declines to those receiving SOC. Median of the maximum declines in HIV-1 RNA were similar for the 40-120 mg once-daily dose groups regardless of baseline Gag polymorphisms. There were no deaths, adverse events leading to discontinuation, or serious adverse events. Conclusions: GSK3532795 demonstrated potent antiviral activity against subtype B (monotherapy or with ATV ± RTV) and subtype C, and was generally well tolerated, which supported continued development of GSK3532795 in subjects with HIV-1 subtype B or subtype C.

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