A5064540365- Platelet Disorders and Treatments
- Antiplatelet Therapy and Cardiovascular Diseases
- Heparin-Induced Thrombocytopenia and Thrombosis
- Medical Imaging Techniques and Applications
- Blood Coagulation and Thrombosis Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- Alzheimer's disease research and treatments
- Blood properties and coagulation
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Cell Adhesion Molecules Research
- Peptidase Inhibition and Analysis
- HER2/EGFR in Cancer Research
- Diabetes Treatment and Management
- Chemical synthesis and pharmacological studies
- Radiopharmaceutical Chemistry and Applications
- Ion channel regulation and function
- Olfactory and Sensory Function Studies
- Cholesterol and Lipid Metabolism
- Computational Drug Discovery Methods
- Metabolomics and Mass Spectrometry Studies
- Synthesis and Characterization of Heterocyclic Compounds
- Cholinesterase and Neurodegenerative Diseases
Merck & Co., Inc., Rahway, NJ, USA (United States)
1992-2022
United States Military Academy
2010-2020
Thomas Jefferson University
1988
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades investigation, the biological roles AMPK and its potential as drug target remain incompletely understood, largely because lack optimized pharmacological tools. We developed MK-8722, potent, direct, allosteric activator all 12 mammalian complexes. In rodents rhesus monkeys, MK-8722-mediated activation skeletal muscle induced robust, durable,...
A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), predominant tau pathology in Alzheimer disease (AD). We describe preclinical characterization NFT 18F-MK-6240.In vitro binding studies were conducted with 3H-MK-6240 tissue slices homogenates from cognitively normal AD human brain donors evaluate affinity selectivity NFTs. Immunohistochemistry phosphorylated was...
Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark several neurodegenerative diseases including Alzheimer's disease. In vivo detection NFTs using PET imaging represents a unique opportunity to develop pharmacodynamic tool accelerate discovery new disease modifying therapeutics targeting pathology. Herein, we present 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), novel tracer for...
β-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of is an essential step in the generation potentially neurotoxic and amyloidogenic Aβ42 peptides Alzheimer9s disease. Although previous mouse studies have shown brain Aβ lowering after BACE1 inhibition, extension such to nonhuman primates or man was precluded by poor potency, penetration, pharmacokinetics available inhibitors. In this study, a novel tertiary carbinamine inhibitor, (TC)-1, assessed unique cisterna magna...
Recent efforts in the field of thrombin inhibitor research have focused on identification compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to optimization 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted modification each three principal components (i.e., P1, P2, P3) comprising series. As result these studies, several potent inhibitors 20, 24, 25) were identified exhibit high levels...
As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via resin-based approach varying P1. By minimizing size and lipophilicity P3 group by incorporating hydrogen-bonding N-terminus or 2-position aromatic ring, prepared number derivatives this exhibit subnanomolar...
The effect of dietary fish oil on myocardial phospholipids and ischemic damage to the heart was studied in rat. Four weeks feeding 5% (i.e., 12 energy percent) menhaden (MO) produced both profound changes fatty acyl composition membranes a significant reduction loss creatine kinase following coronary artery ligation compared with corn (CO). MO diet did not change content either or cholesterol heart. However, resulted elevations percent acids total that were saturated, n-3/n-6 ratio...
The accumulation of amyloid β (Aβ) in Alzheimer's disease is caused by an imbalance production and clearance, which leads to increased soluble Aβ species extracellular plaque formation the brain. Multiple Aβ-lowering therapies are currently development: important goal characterize molecular mechanisms action effects on physiological processing Aβ, as well other precursor protein (APP) metabolites, models approximate human physiology. To this end, we report translation vivo...
Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy safety studies in vivo. Compound 9 showed central pharmacodynamic effects rodent models, evidenced by statistically significant increases apolipoprotein E (apoE) ATP-binding cassette transporter levels brain, along with greatly improved peripheral lipid profile when compared those full dual agonists....
The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development CNS directed therapeutics. We others have investigated muscarinic acetylcholine 4 (M4) positive allosteric modulators (PAMs) for the treatment symptoms associated with neuropsychiatric disorders. In this article, we describe synthesis, vitro, vivo characterization a series central pyridine-related M4 PAMs that can be conveniently radiolabeled...
Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) 3 0.1 nM). However, neither attains significant blood levels upon oral administration rats dogs. With aim improving pharmacokinetic properties via more diverse database, we devised resin-based route for synthesis analogues which P3 residue is replaced with range lipophilic carboxylic amides. Assembly proceeds from common...
The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist the platelet glycoprotein IIb/IIIa, were evaluated in variety canine models. Inhibition ex vivo aggregation responses to ADP collagen observed after acute sequential i.v. administrations 10 500 micrograms/kg or 360-min continuous infusions 1 micrograms/kg/min MK-0383. Hemostatic function normalized within 30 (platelet response collagen, template bleeding times) 90 min sensitivity ADP)...
The rapid identification of protein biomarkers in biofluids is important to drug discovery and development. Here, we describe a general proteomic approach for the proteins that exhibit statistically significant difference abundance cerebrospinal fluid (CSF) before after pharmacological intervention. This approach, differential mass spectrometry (dMS), based on analysis full scan data. dMS workflow does not require complex mixing pooling strategies, or isotope labeling techniques....
The structure-activity relationship of a series orally active glycoprotein IIb/IIIa antagonists containing nitrogen heterocycle grafted onto 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which lactam chiral center has been removed. 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were...
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery the replacement trifluoropropionamide in lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for proved essential. One these novel (13b) also exhibited suitable efficient ex vivo occupancy further development as approach treatment...
The effect of dietary fish oil on cardiac function and responsiveness to alpha- beta-adrenergic receptor agonists was examined in isolated perfused rat hearts. Rats were fed either a standard laboratory diet (SD) or diets containing 5% corn (CO) menhaden (MO) for 4 wk. When as working preparations at varying preloads afterloads, the peak aortic pressures, outputs, coronary flows comparable hearts rats three experimental diets. Inotropic phenylephrine by infusing graded doses drug into heart...
We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to synthesis series imidazole analogues. Compound 6 was chosen for further profiling due its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake FAAH-specific signal in rhesus monkeys is...
Abstract Purpose Programmed cell death-1 receptor (PD-1) and its ligand (PD-L1) are the targets for immunotherapy in many cancer types. Although PD-1 blockade has therapeutic effects, efficacy differs between patients. Factors contributing to this variability PD-L1 expression levels immune cells present tumors. However, it is not well understood how tumor microenvironment impacts response. Thus, imaging of PD-1-expressing interest. This study aims evaluate biodistribution Zirconium-89 ( 89...
[ 11 C]MK-6884 is an M4R-specific PET tracer for quantifying target engagement in brain and providing insights into AD neuropathology.
The synthesis and pharmacological evaluation of 5 (L-738,167), a potent, selective non-peptide fibrinogen receptor antagonist is reported. Compound inhibited the aggregation human gel-filtered platelets with an IC50 value 8 nM was found to be >33000-fold less effective at inhibiting attachment endothelial cells fibrinogen, fibronectin, vitronectin than it platelet aggregation. Ex vivo by >85% 24 h after oral administration dogs 100 μg/kg. extended pharmacodynamic profile exhibited appears...
The efficacy of recombinant vampire bat salivary plasminogen activator (bat-PA) as a thrombolytic agent was compared with that human tissue-type (t-PA) in canine model arterial thrombosis. An occlusive thrombus formed the femoral artery by insertion thrombogenic copper coil; blood flow monitored Doppler meter. Bat-PA and t-PA, when administered 5-minute intravenous infusion (14 nmol/kg), reperfused seven out eight four dogs, respectively. median reperfusion times bat-PA t-PA groups were 24...
The synthesis and pharmacology of 4, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggregation human gel-filtered platelets with an IC50 8 nM demonstrated 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing isoindolinone backbone. Flow cytometry studies revealed that binding to resting is diffusion-controlled process (kon = 3.3 x 10(6) M-1 s-1) binds dog comparable (Kd 0.04 0.07 nM,...