GS-9256(GS-9256) - 药物靶点：NS3 x NS3/NS4A_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

NS3 x NS3/NS4A

作用机制

NS3抑制剂(丙型肝炎病毒非结构蛋白3抑制剂)、NS3/NS4A抑制剂(丙型肝炎病毒NS3/NS4A丝氨酸蛋白酶抑制剂)

治疗领域

感染消化系统疾病

在研适应症-

非在研适应症

慢性丙型肝炎基因型 1

原研机构

Gilead Sciences, Inc.

在研机构-

非在研机构

Gilead Sciences, Inc.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C46H56ClF2N6O8PS

InChIKeyRFGUWOCFYCYEDM-ZOMNBDOOSA-N

CAS号1001094-46-7

关联

4

项与 GS-9256 相关的临床试验

EUCTR2010-020911-35-CZ / Not yet recruitingN/A

A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating 16 and 24 Weeks of Response Guided Therapy With GS-9190, GS-9256, Ribavirin (Copegus®) and Peginterferon Alfa 2a (Pegasys®) in Treatment Naïve Subjects with Chronic Genotype 1 Hepatitis C Virus Infection

开始日期2011-01-17

申办/合作机构

Gilead Sciences, Inc.

NCT01225380 / Completed临床2期

A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating 16 and 24 Weeks of Response Guided Therapy With GS-9190, GS-9256, Ribavirin (Copegus®) and Peginterferon Alfa 2a (Pegasys®) in Treatment Naïve Subjects With Chronic Genotype 1 Hepatitis C Virus Infection (Protocol No. GS-US-196-0123)

This phase 2b study will evaluate the efficacy and safety of 16 and 24 weeks of response-guided duration of therapy with GS-9190 and GS-9256 in combination with Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®). Additionally, the efficacy and safety of 24 weeks of GS-9256 in combination with Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) will be evaluated.

开始日期2010-10-01

申办/合作机构

Gilead Sciences, Inc.

EUCTR2009-013690-18-GB / Not yet recruiting临床2期

A Phase 2, Randomized, Open-Label trial of GS-9256 plus GS-9190 alone and in combination with Ribavirin for 28 days in Treatment Naive Subjects with Chronic Genotype 1 Hepatitis C Virus Infection.

开始日期2010-02-23

申办/合作机构

Gilead Sciences, Inc.

100 项与 GS-9256 相关的临床结果

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100 项与 GS-9256 相关的转化医学

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100 项与 GS-9256 相关的专利（医药）

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8

项与 GS-9256 相关的文献（医药）

2017-07-01·Antiviral Therapy4区 · 医学

Preclinical Characterization of the Novel HCV NS3 Protease Inhibitor GS-9256

4区 · 医学

Article

作者: Kim, Choung U ; Qi, Xiaoping ; Pakdaman, Rowchanak ; Rhodes, Gerry ; Yang, Chris ; Robinson, Margaret ; Cheng, Guofeng ; Mo, Hongmei ; Tian, Yang ; Wang, Yujin ; Delaney, William E ; Yang, Huiling ; Sheng, X Christopher

Background GS-9256 is an inhibitor of HCV NS3 protease with a macrocyclic structure and novel phosphinic acid pharmacophore. Methods Key preclinical properties of GS-9256 including in vitro antiviral activity, cross-resistance and pharmacokinetic properties were investigated in non-human species. Results In genotype (GT) 1b Huh-luc cells with a replicon encoding luciferase, GS-9256 had a mean 50% effective concentration (EC50) value of 20.0 nM, with minimal cytotoxicity. Antiviral activity was similar in a number of additional GT1b and GT1a replicon cell lines. Similar potency was observed in chimeric replicons encoding the NS3 protease of GT1 clinical isolates. GS-9256 was less active in GT2a replicon cells (14.2-fold increase in EC50). Additive to synergistic in vitro antiviral activity was observed when GS-9256 was combined with other agents including interferon-α, ribavirin, NS5B polymerase inhibitors GS-6620 and tegobuvir, as well as the NS5A inhibitor ledipasvir. GS-9256 retained wild-type activity against all tested NS5B and NS5A inhibitor resistance mutations. GS-9256 was metabolically stable in microsomes and hepatocytes of tested species, including rodents, dogs and humans. GS-9256 had high bioavailability in mice (near 100%) and moderate bioavailability in rats (14%), dogs (21%) and monkeys (14%). Elimination half-lives were approximately 2 h in mice, 0.6 h in rats, 5 h in dogs and 4 h in monkey. A study in bile duct-cannulated rats indicated that the major route of elimination is through biliary excretion of unmetabolized GS-9256. Conclusions GS-9256 showed a favourable preclinical profile supportive of clinical development for the treatment of chronic HCV infection in GT1 patients.

2017-04-01·Antiviral Research2区 · 医学

Antiviral response and resistance analysis of treatment-naïve HCV infected patients receiving multiple doses of the NS3 protease inhibitor GS-9256

2区 · 医学

Article

作者: Miller, Michael D ; Delaney, William ; Lawitz, Eric ; Hedskog, Charlotte ; Mo, Hongmei ; Worth, Angela ; Yang, Jenny ; Brainard, Diana M

The NS3 protease inhibitor (PI) GS-9256 has demonstrated antiviral activity in a monotherapy study and in combination with other DAAs for treatment of chronic hepatitis C virus (HCV) infection. The resistance profile of GS-9256 was investigated in a phase 1 monotherapy study of patients with HCV genotype (GT) 1 infection. No PI resistance associated substitutions (RASs) at positions 36, 155, 156, 168 and 170 were observed at baseline by population sequencing (15% cutoff) in the 54 patients enrolled in the study, however the PI RAS Q80K were detected in 41% of patients at baseline. In patients who received 75 mg of the investigational protease inhibitor (PI) GS-9256 BID, 300 mg of GS-9256 QD and 200 mg of GS-9256 BID for three days, NS3 RASs (A156V, R155K, D168G/E/N/V) were observed in 9/21, 3/7 and 8/8 post-treatment, respectively. Q80K was not selected in any patients post-treatment. The mean maximal viral load response was -3.0 ± 0.42 log₁₀ IU/mL HCV RNA in the 200 mg BID cohort. In more than 50% of the patients with RASs detected at Day 4, mutations were no longer detectable by population sequencing at Day 14. One patient had the R155K mutation persist to Week 24. Phenotypic analyses showed that substitutions at R155, A156 and D168 significantly reduced susceptibility to GS-9256. In conclusion, NS3 PI RASs were rapidly selected in the majority of patients receiving GS-9256 as monotherapy, despite undetectable levels at baseline. The R155, A156 and D168 substitutions identified in patients confer reduced susceptibility to GS-9256 and other PIs in vitro.

2014-12-01·Biochimica et Biophysica Acta (BBA) - General Subjects

Binding kinetics, potency, and selectivity of the hepatitis C virus NS3 protease inhibitors GS-9256 and vedroprevir

Article

作者: Schultz, Brian E ; Yang, Huiling ; Delaney, William E ; Jin, Debi ; Wang, Ruth ; Hung, Magdeleine ; Barauskas, Ona ; Hluhanich, Scott ; Corsa, Amoreena C

BACKGROUNDGS-9256 and vedroprevir are inhibitors of the hepatitis C virus NS3 protease enzyme, an important drug target. The potency, selectivity, and binding kinetics of the two compounds were determined using in vitro biochemical assays.METHODSPotency of the compounds against NS3 protease and selectivity against a panel of mammalian proteases were determined through steady-state enzyme kinetics. Binding kinetics were determined using stopped-flow techniques. Dissociation rates were measured using dilution methods.RESULTSGS-9256 and vedroprevir had measured Ki values of 89 pM and 410 pM, respectively, against genotype 1b NS3 protease; Ki values were higher against genotype 2a (2.8 nM and 39 nM) and genotype 3 proteases (104 nM and 319 nM) for GS-9256 and vedroprevir, respectively. Selectivity of GS-9256 and vedroprevir was >10,000-fold against all tested off-target proteases. Association rate constants of 4×10(5)M(-1)s(-1) and 1×10(6)M(-1)s(-1), respectively, were measured, and dissociation rate constants of 4.8×10(-5)s(-1) and 2.6×10(-4)s(-1) were determined.CONCLUSIONSGS-9256 and vedroprevir are potent inhibitors of NS3 protease with high selectivity against off-target proteases. They have rapid association kinetics and slow dissociation kinetics.GENERAL SIGNIFICANCEThe NS3 protease is a key drug target for the treatment of hepatitis C. The potency, selectivity, and binding kinetics of GS-9256 and vedroprevir constitute a biochemical profile that supports the evaluation of these compounds in combination with other direct-acting antivirals in clinical trials for hepatitis C.

100 项与 GS-9256 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12876

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
慢性丙型肝炎基因型 1	临床2期	英国	Gilead Sciences, Inc.	2010-02-01
慢性丙型肝炎基因型 1	临床2期	比利时	Gilead Sciences, Inc.	2010-02-01
慢性丙型肝炎基因型 1	临床2期	德国	Gilead Sciences, Inc.	2010-02-01
慢性丙型肝炎基因型 1	临床2期	法国	Gilead Sciences, Inc.	2010-02-01