A5082671451- Alzheimer's disease research and treatments
- Synthesis and Biological Activity
- Cholinesterase and Neurodegenerative Diseases
- Chemical synthesis and alkaloids
- Advanced Synthetic Organic Chemistry
- Computational Drug Discovery Methods
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Parkinson's Disease Mechanisms and Treatments
- Chemical Synthesis and Analysis
- Plant Gene Expression Analysis
- Antibiotic Resistance in Bacteria
- Phenothiazines and Benzothiazines Synthesis and Activities
- Synthetic Organic Chemistry Methods
- Neuroendocrine regulation and behavior
- Asymmetric Hydrogenation and Catalysis
- Enzyme Catalysis and Immobilization
- Berberine and alkaloids research
- Circadian rhythm and melatonin
- Quinazolinone synthesis and applications
- Crystal Structures and Properties
- Click Chemistry and Applications
- Mineralogy and Gemology Studies
- Stress Responses and Cortisol
- Melanoma and MAPK Pathways
Merck & Co., Inc., Rahway, NJ, USA (United States)
2013-2024
United States Military Academy
2015
Colorado State University
1998-2002
Royal Buckinghamshire Hospital
1994
β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for production Aβ, and BACE1 inhibition thus an attractive target treatment AD. We show that verubecestat (MK-8931) a potent, selective, structurally unique inhibitor reduced plasma, cerebrospinal fluid (CSF), brain concentrations Aβ40, Aβ42, sAPPβ (a direct product enzymatic activity) after...
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are most common genetic cause of familial and sporadic Parkinson's disease (PD). That prevalent mutation, G2019S, leads to increased activity has led a concerted effort identify LRRK2 inhibitors as potential disease-modifying therapy for PD. An internal medicinal chemistry identified several potent highly selective compounds with favorable drug-like properties. Here, we characterize pharmacological properties...
Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over closely related aspartyl protease BACE2, verubecestat has high selectivity BACE1 other key proteases, notably cathepsin D, profoundly lowers CSF brain Aβ...
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains domain and GTPase among other regions. Individuals possessing gain of function mutations in the such as most prevalent G2019S mutation have been associated with an increased risk for development Parkinson's disease (PD). Given this genetic validation inhibition LRRK2 activity potential means affecting progression, our team set out to develop inhibitors test hypothesis. A high throughput screen compound...
Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach the treatment Alzheimer's disease. Despite over decade drug discovery efforts, identification brain-penetrant inhibitors that substantially lower CNS levels following systemic administration remains challenging. In this report we describe structure-based optimization series derived from an iminopyrimidinone scaffold. Application design in tandem with control physicochemical properties...
The first total synthesis of the potent antitumor antibiotic (−)-tetrazomine has been accomplished. A new method for formation allylic amine precursor to an azomethine ylide developed and exploited in efficient [1,3]-dipolar cycloaddition afford key tetracyclic intermediate used (−)-tetrazomine. Several analogues tetrazomine have synthesized tested antimicrobial biochemical activity.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSteric effects inhibiting reactivity. Crystal and molecular structure, spectra, chemistry of trans-chlorocarbonylbis(tri-o-tolylphosphine)iridium(I), related complexesRosemary. Brady, Wilson H. De Camp, Brendan R. Flynn, Michael L. Schneider, J. Douglas. Scott, Vaska, M. F. WernekeCite this: Inorg. Chem. 1975, 14, 11, 2669–2675Publication Date (Print):November 1, 1975Publication History Published online1 May 2002Published inissue 1 November...
Compelling evidence implicates the abnormal accumulation of Aβ in pathogenesis Alzheimer's disease (AD). Inhibition BACE1 to reduce production is a promising approach test amyloid hypothesis. In prior studies healthy volunteers, inhibitor MK-8931 was generally well-tolerated and resulted dose-dependent reduction CSF Ab. Here we report initial characterization pharmacodynamics AD patients. Randomized, double-blind, placebo-controlled, multiple-dose study mild-to-moderate Subjects were...
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Inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization novel series potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type ATP-competitive physicochemical properties were integrated with CNS drug-like through combination structure-based drug...
DNA-encoded library (DEL) technology holds exciting potential for discovering novel therapeutic macrocyclic peptides (MPs). Herein, we describe the development of a DEL-compatible peptide macrocyclization method that proceeds via intramolecular click-condensation between 3-(2-cyano-4-pyridyl)-l-alanine (Cpa) and an N-terminal cysteine. Cyclization takes place spontaneously in buffered aqueous solution affords cyclized products excellent yields. The reaction exhibits broad substrate scope can...
A new method for the formation of allylic amine precursor to an azomethine ylide 1 has been developed and exploited in efficient 1,3-dipolar cycloaddition afford key tetracyclic intermediate used synthesis (-)-tetrazomine (2). Bn=benzyl.
The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe and evolution a picolinamide-derived lead series. Our initial optimization efforts aimed at improving potency CLK2 off-target selectivity compound 1 by modifying heteroaryl C-H hinge linker regions. This resulted in 12 which advanced deep into our operating plan (ROP) before aniline metabolite...
The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort discover pan inhibitors three main families in this class: IMP, VIM, NDM. Herein, describe work improve GN coverage spectrum with imipenem relebactam. This...