BI-653048(BI-653048) - 药物靶点：GR_专利_临床

概要

基本信息

药物类型

小分子化药

别名

BI 653048 BS*H3PO4

+ [3]

靶点

GR

作用方式

调节剂

作用机制

GR调节剂(糖皮质激素受体调节剂)

治疗领域

遗传病与畸形泌尿生殖系统疾病其他疾病+ [2]

在研适应症-

非在研适应症

关节炎内毒素血症胎儿炎症反应综合征

原研机构

Boehringer Ingelheim GmbH

在研机构-

非在研机构

Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim GmbH

Medical University of Vienna

权益机构-

最高研发阶段无进展临床1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/序列

分子式C23H28F4N3O8PS

InChIKeyDPIBBVZDLOOJRM-FTBISJDPSA-N

CAS号1198784-97-2

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关联

3

项与 BI-653048 相关的临床试验

NCT02224105

/ Completed临床1期

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of a BI 653048 BS H3PO4 Capsule Formulation Administered as Multiple Doses of 25 mg to 200 mg Once Daily (qd) for 3 Days Assessing Pharmacodynamics as Endotoxin-induced Inflammatory Response of a Single Intravenous Bolus Administration of 2 ng/kg Body Weight Lipopolysaccharide (LPS). A Randomised, Double-blind Within Dose Groups, Placebo-controlled, Multiple Rising Dose Phase I Trial With Open-label Active Comparator in Healthy Male Subjects

The general aim of the current study was to investigate the safety and tolerability, and pharmacodynamics (endotoxin-induced inflammatory response of a single intravenous bolus administration of 2 ng/kg body weight Escherichia coli lipopolysaccharide (LPS)) of BI 653048 BS H3PO4 capsules in healthy male subjects following oral administration of multiple rising doses of 25 mg to 200 mg over three days compared to the active comparator prednisolone and placebo.
Pharmacodynamics were assessed by investigating the influence of LPS administration on inflammatory parameters. More specifically, it was evaluated whether and to what extent the symptoms induced by LPS challenge can be attenuated by ascending BI 653048 BS H3PO4 doses using prednisolone as positive control and placebo as negative control. A secondary objective was the exploration of pharmacokinetics of BI 653048 BS, the investigation of other pharmacodynamic parameters (biomarker) and of the tolerability of LPS.

开始日期2010-03-01

申办/合作机构

Boehringer Ingelheim GmbH

NCT02217631

/ Completed临床1期

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics (Biomarkers) of BI 653048 BS H3PO4 Capsule Formulation Administered as Multiple Doses of 25 mg to 200 mg qd for 10 Days. A Randomised, Double-blind Within Dose Groups, Placebo-controlled, Multiple Rising Dose Trial With Open-label Active Comparator

The objectives of the trial were to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 653048 BS H3PO4 compared with prednisolone.

开始日期2009-10-01

申办/合作机构

Boehringer Ingelheim GmbH

NCT02217644

/ Completed临床1期

Safety, Tolerability and Pharmacokinetics of BI 653048 H3PO4 Oral Drinking Solution in Healthy Male Volunteers (Dose Range: 0.1 mg - 1500 mg). A Singleblind (Within Dose Groups), Randomised, Placebo-controlled Within Dose Groups, Single Rising Dose Phase I Study

Investigation of safety and tolerability of BI 653048 H3PO4 following the administration of single rising doses of an aqueous solution in healthy male subjects
Pharmacokinetic and pharmacodynamic characteristics of BI 653048, including the investigation of dose proportionality
Investigation of relative bioavailability of capsules versus aqueous solution

开始日期2008-11-01

申办/合作机构

Boehringer Ingelheim GmbH

100 项与 BI-653048 相关的临床结果

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100 项与 BI-653048 相关的转化医学

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100 项与 BI-653048 相关的专利（医药）

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8

项与 BI-653048 相关的文献（医药）

2019-05-04·Expert Opinion on Investigational Drugs2区 · 医学

Clinical profile of the functionally selective glucocorticoid receptor agonist BI 653048 in healthy male subjects

2区 · 医学

Article

作者: Thomson, David ; Harcken, Christian ; Bianchi, Daniel ; Scholl, Paul ; Nabozny, Gerald

BACKGROUNDAn efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC).RESEARCH DESIGN AND METHODSThree Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared.RESULTSTreatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects.CONCLUSIONBI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048.TRIAL REGISTRATIONClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.

2018-03-08·Journal of Medicinal Chemistry1区 · 医学

Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile

1区 · 医学

Article

作者: Ripa, Lena ; Drmota, Tomas ; Edman, Karl ; Lepistö, Matti ; Chang, Hui-Fang ; Hegelund-Myrbäck, Tove ; Bird, James ; Ullah, Victoria ; Harrison, Richard ; Köhler, Christian ; Wissler, Lisa ; Berger, Markus ; Hendrickx, Ramon ; Lawitz, Karolina ; Olsson, Roine I. ; Llinas, Antoni ; Thorne, Philip ; Svanberg, Petter ; Geschwindner, Stefan ; Nikitidis, Antonios ; Dearman, Matthew ; Chapman, Dave ; Malmberg, Jesper ; Edenro, Goran

Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.

2017-11-01·Pharmacological Research2区 · 医学

Selective glucocorticoid receptor modulation inhibits cytokine responses in a canine model of mild endotoxemia

2区 · 医学

Article

作者: Derhaschnig, Ulla ; Bartko, Johann ; Jilma, Bernd ; Harcken, Christian ; Nabozny, Gerald H ; De Vries, Frerich ; Neels, Tania ; Leuschner, Jost

Selective glucocorticoid receptor modulators (GRMs) promise to reduce adverse events of glucocorticoids while maintaining anti-inflammatory potency. The present study tested the anti-inflammatory activity of two novel non-steroidal GRMs (GRM1: BI 607812 BS, GRM2: BI 653048 BS*H3PO4) in comparison to prednisolone in a canine model of low dose endotoxemia. This study compared the anti-inflammatory and pharmacokinetic profile of escalating daily oral doses of GRM1 (1, 2.5, 5 and 10mg/kg) and GRM2 (0.1, 0.25 and 1mg/kg) with prednisolone (0.25 and 0.5mg/kg) and placebo after intravenous infusion of endotoxin (0.1μg/kg) to Beagle dogs. This was followed by a 14-day evaluation study of safety and pharmacokinetics. Endotoxin challenge increased TNF-α ∼2000-fold and interleukin-6 (IL-6) 100-fold. Prednisolone and both GRMs suppressed peak TNF-α and IL-6 by 71-82% as compared with placebo. The highest doses of GRM1 and GRM2 reduced the mean body temperature increase by ∼30%. The endotoxin-induced rise in plasma cortisol was strongly suppressed in all treatment groups. Pharmacokinetics of both GRMs were non-linear. Adverse effects of endotoxemia such as vomiting were mitigated by GRM2 and prednisolone, indicating an antiemetic effect. During the 14-day treatment period, the adverse event profile of both GRMs appeared to be similar to prednisolone. Both GRMs had anti-inflammatory effects comparable to prednisolone and showed good safety profiles. Compounds targeting the glucocorticoid receptor selectively may provide an alternative to traditional glucocorticoids in the treatment of inflammatory disease.

100 项与 BI-653048 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
关节炎	临床1期	奥地利	Medical University of Vienna	2017-11-01
关节炎	临床1期	美国	Boehringer Ingelheim Pharmaceuticals, Inc.	2017-11-01
内毒素血症	临床1期	奥地利	Medical University of Vienna	2017-11-01
内毒素血症	临床1期	美国	Boehringer Ingelheim Pharmaceuticals, Inc.	2017-11-01
胎儿炎症反应综合征	临床1期	-	Boehringer Ingelheim GmbH	2010-03-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02217644 \| NCT02224105 \| NCT02217631 (Pubmed) 人工标引	临床1期	炎症	-	BI 653048 200 mg	(糧窪壓憲顧窪蓋鹽餘襯) = Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone.Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. 觸範觸廠夢膚願鑰餘艱 (壓廠積窪衊鬱網鏇襯鬱 ) 更多	积极	2019-05-04
				prednisolone 20 mg