BMS-986141(BMS-986141) - 药物靶点：PAR-4_在研适应症：冠心病，血栓形成_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PAR-4

作用机制

PAR-4拮抗剂(蛋白酶活化受体4拮抗剂)

治疗领域

心血管疾病

在研适应症

冠心病血栓形成

非在研适应症

急性缺血性卒中动脉粥样硬化脑梗塞+ [3]

原研机构

Bristol Myers Squibb Co.

在研机构

Bristol Myers Squibb Co.

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C27H23N5O5S2

InChIKeyKEEBLYWBELVGPQ-UHFFFAOYSA-N

CAS号1478711-48-6

关联

10

项与 BMS-986141 相关的临床试验

NCT05093790 / Completed临床2期

A Phase 2a Single Dose Study to Evaluate the Effect of BMS-986141 Added on to Aspirin or Ticagrelor or the Combination, on Thrombus Formation in an Ex Vivo Thrombosis Chamber Model in Patients With Stable Coronary Artery Disease and Healthy Participants

The purpose of this study is to assess the effectiveness, safety and tolerability of BMS-986141 added on to aspirin or ticagrelor or the combination on thrombus formation in both healthy participants and participants with stable coronary artery disease.

开始日期2022-03-25

申办/合作机构

Bristol Myers Squibb Co.

NCT03035734 / Withdrawn临床1期

A Randomized Study to Evaluate the Bioavailability of BMS-986141 From a Form B Tablet Formulation Relative to the Form A Reference Tablet in Healthy Participants

Open label, randomized, 4-period crossover study with single doses of BMS-986141 given to healthy female subjects of non-childbearing potential and healthy males.

开始日期2017-01-25

申办/合作机构

Bristol Myers Squibb Co.

NCT02985632 / Withdrawn临床1期

Single-dose Pharmacokinetics of BMS-986141 in Participants With Hepatic Impairment Compared to Healthy Participants

An oral dose of BMS-986141 administered in Hepatic Impairment and Healthy Participants to evaluate pharmacokinetics in this patient population.

开始日期2017-01-11

申办/合作机构

Bristol Myers Squibb Co.

100 项与 BMS-986141 相关的临床结果

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100 项与 BMS-986141 相关的转化医学

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100 项与 BMS-986141 相关的专利（医药）

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6

项与 BMS-986141 相关的文献（医药）

2024-04-01·Arteriosclerosis, Thrombosis, and Vascular Biology

PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies

Article

作者: Wang, Zhaoqing ; Whittington, Beth ; Brittan, Mairi ; Newby, David E ; Merali, Samira ; Nash, Jennifer ; Mills, Nicholas L ; Debono, Samuel ; Chao, Longfei ; Nespoux, Josselin ; Meah, Mohammed N ; Sorbie, Andrew ; Zhang, Yue ; Kozinn, Marc ; Duffin, Rodger ; Dhaun, Neeraj ; Jin, Shiqiang ; Raftis, Jennifer ; Miller, Mark R ; Wang, Beqing ; Kim, Minji ; Bruce, Lorraine

BACKGROUND:BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy.METHODS:Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants.RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)–induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression ( P ≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (−21%; P =0.001) and in patients receiving ticagrelor alone (−28%; P =0.001), aspirin alone (−23%; P =0.018), or both in combination (−24%; P ≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP–induced platelet responses ( P ≤0.001 for all) and total thrombus area under high shear stress conditions ( P ≤0.01 for all). CONCLUSIONS:PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease.REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05093790.

2023-12-31·Platelets

First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants

Article

作者: Seiffert, Dietmar ; Frost, Charles ; Merali, Samira ; Yang, Jing ; Wang, Zhaoqing ; Hawthorne, Dara ; Meadows-Shropshire, Stephanie

BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; N = 60) study; a multiple-ascending-dose (MAD; N = 32) study; and a Japanese MAD (JMAD; N = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25-100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 μM and 25 μM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.

2022-07-14·Journal of Medicinal Chemistry1区 · 医学

Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4

1区 · 医学

Article

作者: Plamondon, Serge ; Martel, Alain ; Sum, Chi Shing ; Bouvier, Michel ; Watson, Carol ; Wexler, Ruth R. ; Guy, Julia ; Priestley, E. Scott ; Ruediger, Edward ; Li, Jianqing ; Gagnon, Marc ; Lavallée, Jean-François ; Gordon, David A. ; Deon, Daniel ; Guarino, Victor R. ; Yang, Jing ; Lapointe, Philippe ; Callejo, Mario ; Dubé, Laurence ; Vetrichelvan, Muthalagu ; Posy, Shana L. ; Marinier, Anne ; Cvijic, Mary Ellen ; Guay, Jocelyne ; Balapragalathan, T. J. ; Richter, Jeremy M. ; Gupta, Anuradha ; Mathur, Arvind ; Rémillard, Roger ; Hua, Ji ; Wong, Pancras ; Banville, Jacques ; Tremblay, François

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.

100 项与 BMS-986141 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14942

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
短暂性脑缺血发作	临床3期	美国	Bristol Myers Squibb Co.	2016-04-25
短暂性脑缺血发作	临床3期	日本	Bristol Myers Squibb Co.	2016-04-25
冠心病	临床2期	英国	Bristol Myers Squibb Co.	2022-03-25
缺血性卒中	临床前	美国	Bristol Myers Squibb Co.	2016-09-01
急性缺血性卒中	临床前	日本	Bristol Myers Squibb Co.	2016-04-25
急性缺血性卒中	临床前	美国	Bristol Myers Squibb Co.	2016-04-25
脑梗塞	临床前	日本	Bristol Myers Squibb Co.	2016-04-25
脑梗塞	临床前	美国	Bristol Myers Squibb Co.	2016-04-25
血栓形成	临床前	美国	Bristol Myers Squibb Co.	2016-04-25
血栓形成	临床前	日本	Bristol Myers Squibb Co.	2016-04-25

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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


NCT05093790 (CTgov)	临床2期	冠心病 \| 血栓形成	58	BMS-986141+Ticagrelor (Arm 1: 90 mg Ticagrelor + 4 mg BMS-986141)	簾願糧鹹醖獵構獵廠範(選遞網窪鏇艱淵齋築餘) = 築鹽夢鑰醖壓構繭選積積簾醖淵夢鹹繭廠窪遞 (醖餘餘憲遞觸襯蓋獵積, 襯糧鏇糧醖鬱構構築憲 ~ 選繭廠簾鹽簾蓋夢廠鏇) 更多	-	2023-12-05
				BMS-986141+Aspirin (Arm 2: 75 mg Aspirin + 4 mg BMS-986141)	簾願糧鹹醖獵構獵廠範(選遞網窪鏇艱淵齋築餘) = 範顧醖膚窪鹹範襯襯願積簾醖淵夢鹹繭廠窪遞 (醖餘餘憲遞觸襯蓋獵積, 簾夢齋製範鬱鏇鏇醖觸 ~ 衊壓選窪選蓋艱積簾憲) 更多
NCT02341638 (Pubmed) 人工标引	临床1期	-	60	BMS-986141 2.5 mg	(齋鹹簾範積憲膚壓積蓋) = 夢艱網糧鑰齋網願蓋獵製遞觸鏇膚壓製夢壓衊 (餘積餘鏇蓋觸積簾衊鹽 ) 更多	积极	2023-12-01
				BMS-986141 150 mg	(齋鹹簾範積憲膚壓積蓋) = 顧壓鏇夢艱襯憲齋艱範製遞觸鏇膚壓製夢壓衊 (餘積餘鏇蓋觸積簾衊鹽 ) 更多
ESC2020	N/A	-	-	BMS-986141	壓鏇憲憲範獵夢願艱蓋(廠鹽夢獵網齋襯願繭顧) = 蓋餘顧鬱鹹夢鏇艱衊鹹襯觸構蓋觸糧壓鹽鬱襯 (範鑰膚鹹蓋簾構築繭艱 ) 更多	-	2020-09-01
				Ticagrelor	壓鏇憲憲範獵夢願艱蓋(廠鹽夢獵網齋襯願繭顧) = 製築獵鑰夢鑰齋願範築襯觸構蓋觸糧壓鹽鬱襯 (範鑰膚鹹蓋簾構築繭艱 ) 更多
NCT02671461 (CTgov)	临床2期	血栓形成 \| 短暂性脑缺血发作 \| 脑梗塞 \| 急性缺血性卒中	16	Placebo+Aspirin	衊夢鑰構淵淵製憲構淵(鹽鹹夢鏇鹽簾範願鑰衊) = 鬱膚齋襯簾廠窪衊憲窪鬱築壓鬱糧觸糧鹽構糧 (觸顧觸繭糧艱醖廠顧膚, 壓簾蓋壓醖艱繭襯製蓋 ~ 糧艱膚獵醖膚艱遞鹹獵) 更多	-	2018-06-12