A5066514556- Cardiomyopathy and Myosin Studies
- Cardiovascular Function and Risk Factors
- Cardiac pacing and defibrillation studies
- Heart Failure Treatment and Management
- Cardiovascular Effects of Exercise
- Muscle Physiology and Disorders
- Neurogenetic and Muscular Disorders Research
- Cardiac electrophysiology and arrhythmias
- Amyotrophic Lateral Sclerosis Research
- Cardiovascular and exercise physiology
- Cardiac Structural Anomalies and Repair
- Viral Infections and Immunology Research
- Muscle activation and electromyography studies
- Congenital Heart Disease Studies
- Myasthenia Gravis and Thymoma
- Microtubule and mitosis dynamics
- Health Systems, Economic Evaluations, Quality of Life
- Cardiac Imaging and Diagnostics
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Cardiovascular Conditions and Treatments
- Trypanosoma species research and implications
- Pulmonary Hypertension Research and Treatments
- Cellular Mechanics and Interactions
- Cardiac Arrest and Resuscitation
- Protist diversity and phylogeny
Cytokinetics (United States)
2016-2025
Lahey Medical Center
2023-2024
Oregon Health & Science University
2023-2024
Brigham and Women's Hospital
2017-2024
Harvard University
2017-2024
University of Michigan
2023-2024
Baim Institute for Clinical Research
2024
Lahey Hospital and Medical Center
2024
Massachusetts General Hospital
2024
Tufts Medical Center
2022
Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, small-molecule, direct activator myosin. Here, show that it binds to the myosin catalytic domain and operates an allosteric mechanism transition rate into strongly actin-bound force-generating state. Paradoxically,...
The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve function in patients with heart failure a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown.We randomly assigned 8256 (inpatients and outpatients) symptomatic chronic an fraction of 35% or less receive (using pharmacokinetic-guided doses 25 mg, 37.5 50 mg twice daily) placebo, addition standard heart-failure therapy. primary outcome was composite first event (hospitalization urgent...
Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and patients with chronic heart failure.This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, efficacy of OM acute failure (AHF).Patients admitted for AHF left ventricular ejection fraction ≤40%, dyspnea, elevated plasma concentrations natriuretic peptides were randomized to receive double-blind, 48-h intravenous infusion placebo or 3...
Abstract Omecamtiv mecarbil is a selective, small-molecule activator of cardiac myosin that being developed as potential treatment for heart failure with reduced ejection fraction. Here we determine the crystal structure in pre-powerstroke state, most relevant state suggested by kinetic studies, both (2.45 Å) and without (3.10 omecamtiv bound. does not change motor mechanism nor it influence structure. Instead, binds to an allosteric site stabilizes lever arm primed position resulting...
Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, next-in-class cardiac myosin inhibitor, may lower gradients and improve these patients.This study aims to evaluate the safety efficacy aficamten patients with oHCM.Patients oHCM LVOT ≥30 mm Hg at rest or ≥50 Valsalva were randomized 2:1 receive (n = 28) placebo 13) 2 dose-finding cohorts. Doses titrated based on ejection fraction...
Hypercontractility of the cardiac sarcomere may be essential for underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel myosin inhibitor that was discovered from optimization indoline compound 1. The important advancement discovery an Indane analogue (12) with less restrictive structure-activity relationship allowed rapid improvement drug-like properties. designed to provide predicted human half-life (t1/2) appropriate once...
BackgroundOne of the major determinants exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten oral selective cardiac myosin inhibitor that reduces gradients by mitigating hypercontractility.MethodsIn this phase 3, double-blind trial, we randomly assigned adults symptomatic HCM to receive aficamten (starting dose, 5 mg; maximum 20 mg)...
Background This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with non-obstructive hypertrophic cardiomyopathy (nHCM). Methods Patients symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤30 mmHg, left ejection fraction [LVEF] ≥60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] >300 pg/mL) received 5–20 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. Results 41 were enrolled (mean ± SD age 56 16...
Background— Therapy for chronic systolic heart failure (sHF) has improved over the past 2 decades, but armamentarium of drugs is limited and consequently sHF remains a leading cause death disability. In this investigation, we examined effects novel cardiac myosin activator, omecamtiv mecarbil (formerly CK-1827452) in different models failure. Methods Results— Two were used: (1) pacing-induced after myocardial infarction (MI-sHF) (2) 1 year pressure overload left ventricular hypertrophy...
In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death patients with and ejection fraction (EF) (≤35%).The purpose this study was evaluate influence baseline EF on therapeutic effect mecarbil.Outcomes treated mecarbil were compared placebo according...
Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients more severe disease are often intolerant of available medical therapies.
<h3>Importance</h3> Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but not consistently improved by any the current guideline-directed medical therapies. <h3>Objective</h3> To determine whether omecamtiv mecarbil, novel direct myosin activator that improves cardiac performance and reduces risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity patients chronic HFrEF. <h3>Design, Setting,...
This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range doses and exposures. At that were (single ≤50 mg or daily dosing ≤10 for 14 17 days), appeared to be safe well tolerated. Adverse events generally mild no more frequent than with placebo. Pharmacokinetic assessments showed dose proportionality over the single administered, pharmacokinetics not affected by administration food...
Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and atrial dilation, which can be associated with progressive heart failure, fibrillation, stroke. Aficamten a next-in-class cardiac myosin inhibitor that reduces obstruction modulating contractility, the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. This study sought investigate effect of aficamten on compared placebo...
Hypertrophic cardiomyopathy (HCM) is an inherited disease of the sarcomere resulting in excessive cardiac contractility. The first-in-class myosin inhibitor, mavacamten, improves symptoms obstructive HCM. Here we present aficamten, a selective small-molecule inhibitor that diminishes ATPase activity by strongly slowing phosphate release, stabilizing weak actin-binding state. Binding to allosteric site on catalytic domain distinct from aficamten prevents conformational changes necessary enter...
Kinesin and dynein are motor proteins that move in opposite directions along microtubules. In this study, we examine the consequences of having kinesin (ciliary outer arm or cytoplasmic) bound to glass surfaces interacting with same microtubule vitro. Although one might expect a balance opposing forces produce little no net movement, find instead microtubules unidirectionally for several microns (corresponding hundreds ATPase cycles by motor) but continually switch between kinesin-directed...
Tubulin is a GTPase that hydrolyzes its bound nucleotide triphosphate after it becomes incorporated into microtubule.The only known consequence of hydrolysis increases the dissociation rate tubulin from end microtubule by 2 orders magnitude.In this study, we investigated whether microtubules composed tubulin-GMPCPP (guanylyl cy,@methylenediphosphate) (a very slowly hydrolyzed GTP analog) or tubulin-GDP exhibit additional structural functional differences.W e show are significantly stiffer...
We report the design, synthesis, and optimization of first, selective activators cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, soluble myosin were designed culminating in discovery omecamtiv mecarbil (24). Compound 24 is currently clinical trials for treatment systolic heart failure.