A5014100235- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- melanin and skin pigmentation
- Receptor Mechanisms and Signaling
- Crystallization and Solubility Studies
- Pancreatic function and diabetes
- X-ray Diffraction in Crystallography
- Metabolism, Diabetes, and Cancer
- Neuropeptides and Animal Physiology
- Alkaloids: synthesis and pharmacology
- Adipose Tissue and Metabolism
- Chemical synthesis and alkaloids
- Diabetes Treatment and Management
- Advanced Synthetic Organic Chemistry
- Coordination Chemistry and Organometallics
- Crystallography and molecular interactions
- Synthesis and Biological Activity
- Asymmetric Synthesis and Catalysis
- Sexual function and dysfunction studies
- Hypothalamic control of reproductive hormones
- Organometallic Complex Synthesis and Catalysis
- Chemical Synthesis and Analysis
- Peptidase Inhibition and Analysis
- Natural Antidiabetic Agents Studies
- Chronic Kidney Disease and Diabetes
Merck & Co., Inc., Rahway, NJ, USA (United States)
2007-2020
Albert Einstein College of Medicine
2002
Imperial College London
2000
The University of Texas at Austin
1998
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,...
By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in control food intake energy expenditure, also modulates erectile function sexual behavior. Evidence supporting this notion is based on several findings: (i) highly selective non-peptide MC4R agonist augments activity initiated by electrical stimulation cavernous nerve wild-type but not Mc4r-null mice; (ii) copulatory behavior enhanced administration...
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic stimulate erectile activity. We report the design development of 1, a potent, selective (1184-fold vs MC3R, 350-fold MC5R), small-molecule agonist MC4 receptor. Pharmacological testing confirms food intake lowering effects MC4R agonism suggests another role for in stimulation
Fibrosis, or the accumulation of extracellular matrix, is a common feature many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-β, as well kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction acylcarnitine found fibrotic tissues. Substantial downregulation PGC1α gene...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis of the Antitumor Alkaloid (+)-Pancratistatin Using β-Azidonation Reaction via a Prochiral 4-Arylcyclohexanone DerivativePhilip Magnus and Iyassu K. SebhatView Author Information Department Chemistry Biochemistry University Texas at Austin, 78712 Cite this: J. Am. Chem. Soc. 1998, 120, 21, 5341–5342Publication Date (Web):May 13, 1998Publication History Received4 February 1998Published online13 May inissue 1 June...
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, caused mechanism-based, dose-dependent reductions in food intake body weight.
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many the beneficial effects exercise weight loss including lipid glucose trafficking. As such, enzyme long interest as target for treatment Type 2 Diabetes Mellitus. We describe optimization β1-selective, liver-targeted AMPK activators their evolution into systemic pan-activators capable acutely lowering mouse models. Identifying surrogates acid...
Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled implicated in the regulation of energy homeostasis. Here, we report biologic effects a highly optimized BRS-3 agonist, (2<i>S</i>)-1,1,1-trifluoro-2-[4-(1<i>H</i>-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1<i>H</i>-imidazol-2-yl)propan-2-ol (MK-5046). Single oral doses MK-5046 inhibited 2-h and overnight food intake increased fasting metabolic rate wild-type but not <i>Brs3</i> knockout mice. Upon...
Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise occur within skeletal muscle other organs. There is interest discovering a pharmacologic mimetic could imbue wellness alleviate disease burden. However, molecular physiology by which signals response highly complex, making it challenging identify single target for pharmacological mimicry. The current studies evaluated transcriptome muscle, heart, liver,...
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid carbohydrate resulting from insulin resistance leads to hyperglycemia, the hallmark type 2 diabetes mellitus (T2DM). While pharmacological activation AMPK is anticipated improve these parameters, discovery selective, direct activators has proven challenging. We now describe hit-to-lead effort potent selective class benzimidazole-based...
Metabolic dysregulation and mitochondrial dysfunction are important features of acute chronic tissue injury across species, human genetics preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated protein kinase (AMPK) may be an effective therapeutic target for kidney disease (CKD). We have recently disclosed a pan-AMPK activator, MK-8722, was shown to beneficial effects in models. In this study we investigated MK-8722 progressive rat model diabetic...
A method is described for the evaluation of drug concentrations in plasma and brain from treated rats. The analyte recovered or homogenate by liquid-liquid extraction subsequently analyzed liquid chromatography/tandem mass spectrometry (LC/MS/MS). simple experimental protocol renders procedure valuable obtaining information rapidly on penetration exposure specific classes compounds. This methodology has been applied to evaluate with 30 different compounds same discovery program. In an...