New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans

Garonzik, Samira M.; Wang, Zhaoqing; Frost, Charles A; Callejo, María; Hedrick, Michael N.; Hui, Lester; Shropshire, Stephanie Meadows; Xu, Ke; Bouvier, Michel; DeSouza, Mary M.; Yang, Jing

doi:10.1080/09537104.2022.2088719

Cited by 10 publications

(10 citation statements)

References 23 publications

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“…In phase I human clinical trials, BMS-986120 (1) and BMS-986141 were safe and well tolerated in healthy participants over a wide range. 20,22 However, at this time, the BMS compounds have not advanced further in clinical development and larger clinical trials would ultimately be needed to establish safety.…”

Section: ■ Par4 As a Therapeutic Targetmentioning

confidence: 99%

“…PAR1 has a greater affinity for thrombin than PAR4, but despite early clinical promise, the addition of vorapaxar (the only licensed PAR1 antagonist) to standard care failed to meet its primary efficacy outcome in patients with acute coronary syndrome and was associated with an excess of major bleeding, especially intracranial hemorrhage, in phase 3 clinical trials. , Therefore, attention has since turned toward PAR4 as a potential thrombin receptor therapeutic target. Bristol–Myers–Squibb (BMS) developed PAR4 antagonists BMS-986120 ( 1 ) and BMS-986141 as antithrombotic agents with high potency and specificity for thrombin activation of PAR4 over PAR1. − PAR4 antagonists are hypothesized to have a lower bleeding risk than PAR1 antagonists because PAR4 acts at a later stage in the platelet activation process than PAR14. Importantly, in a cynomolgus monkey arterial thrombosis model, BMS-986120 ( 1 ) demonstrated potent and highly efficacious antithrombotic activity .…”

Section: Par4 As a Therapeutic Targetmentioning

confidence: 99%

“…BMS-986120 ( 1 ) also exhibited a low bleeding liability and a markedly wider therapeutic window compared to that of clopidogrel tested in the same nonhuman primate model. In phase I human clinical trials, BMS-986120 ( 1 ) and BMS-986141 were safe and well tolerated in healthy participants over a wide range. , However, at this time, the BMS compounds have not advanced further in clinical development and larger clinical trials would ultimately be needed to establish safety.…”

Section: Par4 As a Therapeutic Targetmentioning

confidence: 99%

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Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening

Smith,

Cassada,

Von Bredow

et al. 2024

ACS Pharmacol. Transl. Sci.

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Here, we demonstrate a structure-based small molecule virtual screening and lead optimization pipeline using a homology model of a difficult-to-drug G-protein-coupled receptor (GPCR) target. Protease-activated receptor 4 (PAR4) is activated by thrombin cleavage, revealing a tethered ligand that activates the receptor, making PAR4 a challenging target. A virtual screen of a make-on-demand chemical library yielded a one-hit compound. From the single-hit compound, we developed a novel series of PAR4 antagonists. Subsequent lead optimization via simultaneous virtual library searches and structurebased rational design efforts led to potent antagonists of thrombin-induced activation. Interestingly, this series of antagonists was active against PAR4 activation by the native protease thrombin cleavage but not the synthetic PAR4 agonist peptide AYPGKF.

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Section: ■ Par4 As a Therapeutic Targetmentioning

confidence: 99%

Section: Par4 As a Therapeutic Targetmentioning

confidence: 99%

Section: Par4 As a Therapeutic Targetmentioning

confidence: 99%

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Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening

Smith,

Cassada,

Von Bredow

et al. 2024

ACS Pharmacol. Transl. Sci.

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“…Both preclinical and early clinical studies have demonstrated PAR4 antagonism has antithrombotic efficacy and may have minimal impact on bleeding. 16,18–22…”

mentioning

confidence: 99%

“…Both preclinical and early clinical studies have demonstrated PAR4 antagonism has antithrombotic efficacy and may have minimal impact on bleeding. 16,[18][19][20][21][22] We have previously demonstrated in healthy volunteers that PAR4 antagonism reduces thrombus formation in an ex vivo model of acute arterial injury 18 as well as demonstrated that PAR4 antagonism provides additive antithrombotic effects when used in combination with factor Xa inhibition. 23 However, the antithrombotic efficacy of PAR4 antagonism in patients with coronary artery disease and its additive benefit to contemporary antiplatelet therapy has not been established.…”

mentioning

confidence: 99%

PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies

Nash,

Meah,

Whittington

et al. 2024

ATVB

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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.

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The thrombin receptor PAR4 supports visceral adipose tissue inflammation

Kleeschulte,

Fischinger,

Öhlke

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Thrombin inhibition suppresses adiposity, WAT inflammation and metabolic dysfunction in mice. Protease-activated receptor (PAR)1 does not account for thrombin-driven obesity, so we explored the culprit role of PAR4 in this context. Male WT and PAR-4-/- mice received a high fat diet (HFD) for 8 weeks, WT controls received standard chow. Body fat was quantified by NMR. Epididymal WAT was assessed by histology, immunohistochemistry, qPCR and lipase activity assay. 3T3-L1 preadipocytes were differentiated ± thrombin, acutely stimulated ± PAR4 activating peptide (AP) and assessed by immunoblot, qPCR and U937 monocyte adhesion. Epicardial adipose tissue (EAT) from obese and lean patients was assessed by immunoblot. PAR4 was upregulated in mouse WAT under HFD. PAR4-/- mice developed less visceral adiposity and glucose intolerance under HFD, featuring smaller adipocytes, fewer macrophages and lower expression of adipogenic (leptin, PPARγ) and pro-inflammatory genes (CCL2, IL-1β) in WAT. HFD-modified activity and expression of lipases or perilipin were unaffected by PAR4 deletion. 3T3-L1 adipocytes differentiated with thrombin retained Ki67 expression, further upregulated IL-1β and CCL2 and were more adhesive for monocytes. In mature adipocytes, PAR4-AP increased phosphorylated ERK1/2 and AKT, upregulated Ki67, CCl2, IL-β and hyaluronan synthase 1 but not TNF-α mRNA, and augmented hyaluronidase-sensitive monocyte adhesion. Obese human EAT expressed more PAR4, CD68 and CD54 than lean EAT. PAR4 upregulated in obesity supports adipocyte hypertrophy, WAT expansion and thrombo-inflammation. The emerging PAR4 antagonists provide a therapeutic perspective in this context beyond their canonical antiplatelet action.

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New oral protease-activated receptor 4 antagonist BMS-986120: tolerability, pharmacokinetics, pharmacodynamics, and gene variant effects in humans

Cited by 10 publications

References 23 publications

Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening

Discovery of Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Using Ultralarge Virtual Screening

PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies

The thrombin receptor PAR4 supports visceral adipose tissue inflammation

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