A5102854109- Peroxisome Proliferator-Activated Receptors
- Adipose Tissue and Metabolism
- Microbial Natural Products and Biosynthesis
- Carbohydrate Chemistry and Synthesis
- Computational Drug Discovery Methods
- Blood Coagulation and Thrombosis Mechanisms
- Plant biochemistry and biosynthesis
- Metabolism, Diabetes, and Cancer
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Atrial Fibrillation Management and Outcomes
- Parkinson's Disease Mechanisms and Treatments
- Eicosanoids and Hypertension Pharmacology
- Diabetes Treatment and Management
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Synthesis of Organic Compounds
- Synthetic Organic Chemistry Methods
- Synthesis and Biological Evaluation
- Pharmacogenetics and Drug Metabolism
- Plant Gene Expression Analysis
- Catalytic Cross-Coupling Reactions
- Sulfur-Based Synthesis Techniques
- Drug Transport and Resistance Mechanisms
- Cancer Risks and Factors
Merck & Co., Inc., Rahway, NJ, USA (United States)
2013-2024
Wake Forest University
2008
Cornell University
1989-2001
University of Delaware
2001
Australian National University
2000
Harvard University
1996-1997
University of South Alabama
1986-1987
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and clinically validated target for the treatment hypercholesterolemia coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these obtain extremely potent bi- tricyclic PCSK9 inhibitor peptides. Optimized molecules 44 demonstrated sufficient oral bioavailability maintain therapeutic levels in rats cynomolgus monkeys after dosing...
Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low lipoprotein-cholesterol, but despite nearly 2 decades effort, an oral inhibitor is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable small-molecule drug design. Methods: Novel mRNA display screening technology was used...
Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well potency. Despite this, analysis of large body data indicates lipophilicity no consistent directional impact dose. This can be rationalized based the interplay effects individual parameter values in pharmacokinetic equations. We believe this undermines effectiveness strategies target specific ranges for which plays such role. As result, our research organization longer leverages common approach...
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling progressive neurodegenerative disorder whose current therapies are limited in scope efficacy. In this report, we describe rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated the discovery of brain-penetrant, candidate-quality molecules as represented compounds 22 24. These exhibit remarkable selectivity against...
Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR)γ agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPARγ modulators (SPPARγMs) have identified that efficacy comparable with full improved tolerability in preclinical species. The results structural studies support the proposition SPPARγMs interact differently from agonists, thereby providing a physical basis for novel activities....
A series of benzimidazolone carboxylic acids and oxazolidinediones were designed synthesized in search selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone pioglitazone, currently marketed full agonist drugs. Structure-activity relationships these potent highly SPPARγMs studied a focus on their unique partial agonists or modulators. variety methods, such X-ray...
Insulin-induced hypoglycemia in diabetes is associated with impaired glucagon secretion. In this study, we tested whether stimulation of GPR119, a G-protein–coupled receptor expressed pancreatic islet as well enteroendocrine cells and previously shown to stimulate insulin incretin secretion, might enhance secretion during hypoglycemia. the GPR119 agonists were applied isolated islets or perfused pancreata assess hypoglycemic hyperglycemic conditions. Insulin infusion clamps performed without...
G. N. Burkhardt and H. Wood, J. Chem. Soc., 1929, 141 DOI: 10.1039/JR9290000141
Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment Parkinson's disease. We previously disclosed discovery an indazole series lead that demonstrated both safety and translational risks. The risks were hypothesized to be unknown origin, so structural diversity in subsequent chemical matter was prioritized. identified due low brain Kp
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARγ has been prevented due adverse effects including weight gain, edema, and increased risk congestive heart failure. Selective modulators (SPPARγMs) have identified that antidiabetic efficacy reduced toxicity in preclinical species. In comparison with full agonists, SPPARγM 6 (MK0533) displayed diminished maximal activity (partial agonism) cell-based...
Two orthogonal approaches for hit identification in drug discovery are large-scale vitro and silico screening. In recent years, due to the emergence of new targets a rapid increase size readily synthesizable chemical space, there is growing emphasis on integration two techniques improve finding efficiency. Here, we highlight three examples projects at Merck & Co., Inc., Kenilworth, NJ, USA which different virtual screening (VS) techniques, each specifically tailored leverage knowledge...
"Operative mortality" is a term frequently encountered in surgical literature and used, apparently, to include the proportion of deaths which occur soon after operations. The reports percentage quickly follow operations are regarded as operative mortality vary so widely for same operation by different surgeons that it evident there has been no attempt standardize expression nor explain its meaning or inclusion. Some writers report "hospital mortality," others simply "mortality"; former...
his Olympic victory; also the news of death Orillo was carried from Damiata in Greece to Egypt by a pigeon.During Crusades, as at siege Jerusalem and during crusade St. Louis, pigeons were made useful service war similar manner.Marco Polo, who travelled Asia between 1275 1295, writing on falconry, stated (according Boni, 1845): "Each bird belonging sovereign Barons has tablet silver its feet, with name that owner inscribed so wherever caught it can be returned him."Thomas Nuttall 1840 wrote:...
Nitroalkene fatty acids are potent endogenous ligand activators of PPARγ-dependent transcription. Previous studies with the naturally occurring regioisomers nitrolinoleic acid revealed that isomers not equivalent respect to PPARγ activation. To gain further insight into structure−activity relationships between nitroalkenes and PPARγ, we examined additional derived from oleic acid, 9-nitrooleic (E-9-NO2-18:1 [1]) 10-nitrooleic (E-10-NO2-18:1 [2]), several synthetic nitrated enoic variable...
Process safety is an important consideration not only when conducting reactions on manufacturing scale, but also lab and kilo scale. This contribution presents a discussion of Merck's Reaction Review policy, originally specific to Chemistry now applied broadly across the whole chemistry organization. Details policy case studies are included.
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...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTA New Strategy for Stereocontrol of Cation−Olefin Cyclization. The First Chemical Emulation the A/B-trans-9,10-syn-Folding Pathway Steroid Biosynthesis from 2,3-OxidosqualeneE. J. Corey and Harold B. WoodView Author Information Department Chemistry Biology Harvard University, Cambridge, Massachusetts 02138 Cite this: Am. Chem. Soc. 1996, 118, 47, 11982–11983Publication Date (Web):November 27, 1996Publication History Received19 September...
A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated number metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities FIXa protein. Microgram quantities interest then isolated through microisolation analytical capabilities, structurally characterized using MicroCryoProbe heteronuclear 2D NMR...