Delving into the Latest Updates on BMS-986141 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PAR-4

Mechanism

PAR-4 antagonists(Protease-activated receptor-4 antagonists)

Therapeutic Areas

Cardiovascular Diseases

Active Indication

Coronary Artery DiseaseThrombosis

Inactive Indication

Acute Ischemic StrokeAtherosclerosisBrain Infarction+ [2]

Originator Organization

Bristol Myers Squibb Co.

Active Organization

Bristol Myers Squibb Co.

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC27H23N5O5S2

InChIKeyKEEBLYWBELVGPQ-UHFFFAOYSA-N

CAS Registry1478711-48-6

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

31 Dec 2023·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

Author: 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.

14 Jul 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: Watson, Carol ; Martel, Alain ; Plamondon, Serge ; Bouvier, Michel ; Sum, Chi Shing ; Wexler, Ruth R. ; Priestley, E. Scott ; Guy, Julia ; Ruediger, Edward ; Li, Jianqing ; Gagnon, Marc ; Lavallée, Jean-François ; Gordon, David A. ; Deon, Daniel ; Yang, Jing ; Lapointe, Philippe ; Guarino, Victor R. ; Callejo, Mario ; Dubé, Laurence ; Vetrichelvan, Muthalagu ; Posy, Shana L. ; Guay, Jocelyne ; Cvijic, Mary Ellen ; Marinier, Anne ; 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 Deals associated with BMS-986141

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14942

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronary Artery Disease	Phase 2	GB	Bristol Myers Squibb Co.	25 Mar 2022
Atherosclerosis	Preclinical	-	Bristol Myers Squibb Co.	01 Nov 2016
Acute Ischemic Stroke	Preclinical	US	Bristol Myers Squibb Co.	25 Apr 2016
Acute Ischemic Stroke	Preclinical	JP	Bristol Myers Squibb Co.	25 Apr 2016
Brain Infarction	Preclinical	JP	Bristol Myers Squibb Co.	25 Apr 2016
Brain Infarction	Preclinical	US	Bristol Myers Squibb Co.	25 Apr 2016
Ischemic Attack, Transient	Preclinical	JP	Bristol Myers Squibb Co.	25 Apr 2016
Ischemic Attack, Transient	Preclinical	US	Bristol Myers Squibb Co.	25 Apr 2016
Thrombosis	Preclinical	JP	Bristol Myers Squibb Co.	25 Apr 2016
Thrombosis	Preclinical	US	Bristol Myers Squibb Co.	25 Apr 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05093790 (CTgov)	Phase 2	Thrombosis \| Coronary Artery Disease	58	BMS-986141+Ticagrelor (Arm 1: 90 mg Ticagrelor + 4 mg BMS-986141)	wqamrraniz(viurrcbrkv) = ebbqseepcq jlmsyozcsh (xjvhufewwz, ghyzynvcug - jvjtzqyhds) View more	-	05 Dec 2023
				BMS-986141+Aspirin (Arm 2: 75 mg Aspirin + 4 mg BMS-986141)	wqamrraniz(viurrcbrkv) = olsbiksyst jlmsyozcsh (xjvhufewwz, esdpkqksla - xgtoabywva) View more
NCT02341638 (Pubmed) Manual	Phase 1	-	60	BMS-986141 2.5 mg	(bttijouvil) = raafgzoqva fjkpcmubny (ixilyxnuno ) View more	Positive	01 Dec 2023
				BMS-986141 150 mg	(bttijouvil) = qrvylnmcmh fjkpcmubny (ixilyxnuno ) View more
ESC2020	Not Applicable	-	-	BMS-986141	esmucqjhal(zszwagxrnh) = viavnekmwp ebajydthcd (vyfkmyzxof ) View more	-	01 Sep 2020
				Ticagrelor	esmucqjhal(zszwagxrnh) = rlkmgrmbgz ebajydthcd (vyfkmyzxof ) View more
NCT02671461 (CTgov)	Phase 2	Thrombosis \| Ischemic Attack, Transient \| Brain Infarction \| Acute Ischemic Stroke	16	Placebo+Aspirin	nkopkoxfaz(hjrhnoorra) = eqbrbpbife liuwtdhlxm (rgdwbdukby, yrqmjxocia - jdggtpqeha) View more	-	12 Jun 2018