BMS-986141 / BMS - LARVOL DELTA

PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies. (PubMed, Arterioscler Thromb Vasc Biol) - P2 | "BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790."

Journal • Cardiovascular • Coronary Artery Disease • Heart Failure • Hematological Disorders • Thrombosis

A Study to Evaluate BMS-986141 Added on to Aspirin or Ticagrelor or the Combination, on Thrombus Formation in a Thrombosis Chamber Model in Participants With Stable Coronary Artery Disease and Healthy Participants (clinicaltrials.gov) - P2 | N=58 | Completed | Sponsor: Bristol-Myers Squibb | Phase classification: P2a ➔ P2

Phase classification • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Thrombosis

A Study to Evaluate BMS-986141 Added on to Aspirin or Ticagrelor or the Combination, on Thrombus Formation in a Thrombosis Chamber Model in Participants With Stable Coronary Artery Disease and Healthy Participants (clinicaltrials.gov) - P2a | N=58 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed

Trial completion • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Thrombosis

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. (PubMed, Platelets) - P1 | "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."

Clinical • Journal • P1 data • PK/PD data

Discovery of Two Novel Antiplatelet Clinical Candidates (BMS-986120 and BMS-986141) That Antagonize Protease-Activated Receptor 4. (PubMed, J Med Chem) - "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."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

A Study to Evaluate BMS-986141 Added on to Aspirin or Ticagrelor or the Combination, on Thrombus Formation in a Thrombosis Chamber Model in Participants With Stable Coronary Artery Disease and Healthy Participants (clinicaltrials.gov) - P2a | N=55 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting | Trial completion date: Mar 2022 ➔ Sep 2022 | Initiation date: Oct 2021 ➔ Mar 2022 | Trial primary completion date: Mar 2022 ➔ Sep 2022

Enrollment open • Preclinical • Trial completion date • Trial initiation date • Trial primary completion date • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Thrombosis

Inhibitors of protease activated receptor 4 (PAR4): a review of recent patents (2013-2021). (PubMed, Expert Opin Ther Pat) - "Most the recent patents and literature focus on PAR4 selective inhibitors, and BMS-986120 and BMS-986141, which were developed by BMS, have entered clinical trials. With the deep understanding of the crystal structures and biological functions of PAR4, we believe that many other novel types of molecules targeting PAR4 would enter the clinical studies or the market."

Journal • Review • Cardiovascular • Hematological Disorders • Pulmonary Embolism • Respiratory Diseases

A Study to Evaluate BMS-986141 Added on to Aspirin or Ticagrelor or the Combination, on Thrombus Formation in a Thrombosis Chamber Model in Participants With Stable Coronary Artery Disease and Healthy Participants (clinicaltrials.gov) - P2a; N=55; Not yet recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P2a trial • Preclinical • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Thrombosis

Synthesis and evaluation of novel and potent protease activated receptor 4 (PAR4) antagonists based on a quinazolin-4(3H)-one scaffold. (PubMed, Eur J Med Chem) - "To date, only two PAR4 antagonists, BMS-986120 and BMS-986141 have entered clinical trials for thrombosis...In summary, the quinazolin-4(3H)-one-based analogues are the first reported chemotypes with excellent activity and selectivity against PAR4, and, in the current study, we expanded the structural diversity of PAR4 antagonists. The two compounds, 13 and 30g, found in our study could be promising starting points with great potential for further research in antiplatelet therapy."

Journal • Cardiovascular • Hematological Disorders • Myocardial Infarction • Thrombosis

[VIRTUAL] BMS-986141, a Selective PAR4 Antagonist, Reduces Platelet Deposition in a Microfluidic Thrombosis Assay (ISTH 2021) - "fluorescence intensity) Conclusions : BMS-986141 is a highly specific antagonist of PAR4. This small molecule reduced platelet deposition in a microfluidic assay of perfused CTI-treated whole blood over patterned surfaces of vWF/TF, which simulate conditions of arterial thrombosis."

Cardiovascular • Hematological Disorders • Thrombosis

[VIRTUAL] BMS-986141, a Selective PAR4 Antagonist, Reduces Platelet Deposition in a Microfluidic Thrombosis Assay (ISTH 2021) - "fluorescence intensity) Conclusions : BMS-986141 is a highly specific antagonist of PAR4. This small molecule reduced platelet deposition in a microfluidic assay of perfused CTI-treated whole blood over patterned surfaces of vWF/TF, which simulate conditions of arterial thrombosis."

Cardiovascular • Hematological Disorders • Thrombosis

[VIRTUAL] Antithrombotic Effects of Combined Protease-activated Receptor-4 Antagonism and Factor Xa Inhibition (AHA 2020) - "Ex vivo platelet activation, platelet aggregation and thrombus formation were measured in low-shear and high-shear stress perfusion chambers after extracorporeal infusion of (1) vehicle (99% polyethylene glycol 400/1% Kollidon VA 64), (2) low-dose apixaban (20 ng/mL), (3) high-dose apixaban (80 ng/mL), (4) BMS-986141 (400 ng/mL), (5) low-dose apixaban and BMS-968141, and (6) high-dose apixaban and BMS-986141 in 6 sequential studies performed in random order. BMS-986141 reduces platelet-rich thrombus formation especially under conditions of high-shear stress. This suggests the potential for additive efficacy of combination PAR4 antagonism and factor Xa inhibition in the prevention of atherothrombotic events."

Thrombosis

Protease activated receptor 4 (PAR4) antagonists: Research progress on small molecules in the field of antiplatelet agents. (PubMed, Eur J Med Chem) - "Currently, research on PAR4 antagonists is of increasing interest in the field of antiplatelet agents. This article provides an overview of the discovery and development of small-molecule antagonists of PAR4 as novel antiplatelet agents, including structure-activity relationship (SAR) analysis, progress of structure and bioassay optimization, and the latest structural and/or clinical information of representative small-molecule antagonists of PAR4."

Journal • Review • Cardiovascular • Myocardial Infarction • Thrombosis

[VIRTUAL] Favorable therapeutic index of an orally-active small-molecule antagonist of the platelet protease-activated receptor-4, BMS-986141, compared with the P2Y12 antagonist ticagrelor in cynomolgus monkeys (ESC 2020) - "Comparable antithrombotic efficacy was observed between BMS-986141 and ticagrelor in monkeys. BMS-986141 exhibited lower MBT compared with ticagrelor at equivalent antithrombotic doses. This study suggests that PAR4 antagonism provides a potentially safer antiplatelet therapy."

Cardiovascular • Thrombosis • F2

Antithrombotic Effects of Combined PAR (Protease-Activated Receptor)-4 Antagonism and Factor Xa Inhibition. (PubMed, Arterioscler Thromb Vasc Biol) - "In the presence of factor Xa inhibition, PAR4 antagonism with BMS-986141 further reduces thrombus formation, especially under conditions of high shear stress. This suggests the potential for additive efficacy of combination PAR4 antagonism and factor Xa inhibition in the prevention of atherothrombotic events."

Journal • Cardiovascular • Hematological Disorders • Psychiatry • Thrombosis