A5027177687- Inflammatory mediators and NSAID effects
- Estrogen and related hormone effects
- Synthesis and biological activity
- Receptor Mechanisms and Signaling
- Asthma and respiratory diseases
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Neuropeptides and Animal Physiology
- Synthesis of β-Lactam Compounds
- Bioactive Compounds and Antitumor Agents
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and Reactions of Organic Compounds
- Immune Response and Inflammation
- Adenosine and Purinergic Signaling
- Antimicrobial Peptides and Activities
- Eicosanoids and Hypertension Pharmacology
- Synthesis and Biological Evaluation
- Protein Degradation and Inhibitors
- Peroxisome Proliferator-Activated Receptors
- Cancer, Stress, Anesthesia, and Immune Response
- Epigenetics and DNA Methylation
- HIV/AIDS drug development and treatment
- Histone Deacetylase Inhibitors Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
Tri-Institutional Therapeutics Discovery Institute
2019-2024
Rockefeller University
2024
Bridge Pharma (United States)
2022-2023
Merck & Co., Inc., Rahway, NJ, USA (United States)
1988-2017
Merck Canada Inc. (Canada)
1992-2011
TransCanada (Canada)
1997-2011
Merck (Japan)
2000-2003
University of Virginia
2001
United States Military Academy
1988
Weizmann Institute of Science
1986
Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, its amino sequence found to be 52 percent identical growth secretagogues. The macrolide antibiotic erythromycin also interacted with cloned receptor,...
The discoveries that cyclooxygenase (COX)-2 is an inducible form of COX involved in inflammation and COX-1 the major isoform responsible for production prostaglandins (PGs) gastrointestinal tract have provided a rationale development specific COX-2 inhibitors as new class anti-inflammatory agents with improved tolerability. In present study, preclinical pharmacological biochemical profiles rofecoxib [Vioxx, also known MK-0966, 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone], orally...
Mutations in the human adenomatous polyposis (APC) gene are causative for familial (FAP), a rare condition which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. The APC is tumor suppressor that has been termed "gatekeeper gene" In addition 100% mutation rate FAP patients, mutated >80% of sporadic and intestinal cancers. Apc mice either by chemical carcinogenesis, resulting Min mouse Apcdelta850, or heterologous recombination, Apcdelta716...
1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) at least 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 > 50 microM). Indomethacin potent inhibitor both 18 3 26 6 under same assay conditions. The large...
Challenge of human peripheral blood leukocytes with ionophore A23187 resulted in leukotriene (LT) synthesis, a decrease total cellular 5-lipoxygenase activity, and change the subcellular localization enzyme. In homogenates from control cells, greater than 90% activity protein was localized cytosol (100,000 X g supernatant). Ionophore challenge (2 microM) loss approximately 55% enzymatic 35% enzyme cytosol. Concomitantly, there an accumulation inactive membrane pellets) which accounted for at...
The cysteinyl leukotrienes (CysLTs) are important mediators of human asthma. Pharmacologic and clinical studies show that the CysLTs exert most their bronchoconstrictive proinflammatory effects through activation a putative, 7-transmembrane domain, G-protein–coupled receptor, CysLT1 receptor. initial molecular characterization receptor showed by in situ hybridization, presence messenger RNA (mRNA) lung smooth-muscle cells macrophages. We confirmed results these hybridization analyses for...
The enzyme 5-lipoxygenase (5-LO) catalyzes the first two reactions in pathway leading to formation of leukotrienes from arachidonic acid. Leukotrienes are potent acid metabolites possessing biological activities that suggest a role pathophysiology allergic and inflammatory diseases. To obtain structural information about 5-LO for use developing anti-inflammatory chemotherapeutic agents, was purified human polymorphonuclear leukocytes amino sequences were determined several cyanogen...
G protein-coupled receptors are commonly thought to bind their cognate ligands and elicit functional responses primarily as monomeric receptors. In studying the recombinant gamma-aminobutyric acid, type B (GABAB) receptor (gb1a) a GABAB-like orphan (gb2), we observed that both functionally inactive when expressed individually in multiple heterologous systems. Characterization of tissue distribution each by situ hybridization histochemistry rat brain revealed co-localization gb1 gb2...
The NS5A protein plays a critical role in the replication of HCV and has been focus numerous research efforts over past few years. inhibitors have shown impressive vitro potency profiles replicon assays, making them attractive components for inclusion all oral combination regimens. Early work arena led to discovery our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical...
Previous studies involving transfection of cDNAs for 5-lipoxygenase-activating protein (FLAP) and 5-lipoxygenase into osteosarcoma cells have shown that both these proteins are essential leukotriene synthesis (Dixon, R. A. F., Diehl, E., Opas, Rands, Vickers, P. J., Evans, J. Gillard, W., Miller, D. K. (1990) Nature 343, 282-284). In the present study we show FLAP is in a variety known to produce leukotrienes, but absent from number which do not synthesize leukotrienes. Furthermore,...
Human prostaglandin G/H synthase (hPGHS)-1 and hPGHS-2, key enzymes in the formation of prostanoids from arachidonic acid, were expressed at high levels COS-7 cells using a T7 RNA polymerase/vaccinia virus expression system. The open reading frame hPGHS-2 cloned into vaccinia without its natural 5' 3' untranslated regions directed only low enzyme activity cells. High-level was achieved by appending region hPGHS-1 to frame, with subsequent hybrid mRNA virus. Enzymatically active recombinant...
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 7 were found to be DP (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives high clearance rates in rats. Rat bile duct cannulation studies revealed that concentrations parent drug present biliary...
The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid (AML), but its therapeutic potential remains unclear. We describe potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from by blocking YEATS domain interaction with acylated histones. Cell lines primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen...
Abstract: Galanin is a 29‐ or 30‐amino acid peptide with wide‐ranging effects on hormone release, feeding behavior, smooth muscle contractility, and somatosensory neuronal function. Three distinct galanin receptor (GALR) subtypes, designated GALR1, 2, 3, have been cloned from the rat. We report here cloning of human GALR2 GALR3 genes, an initial characterization their pharmacology respect to radioligand binding signal transduction pathways, profile expression in brain peripheral tissues....
Caspase-3 is synthesized as a dormant proenzyme and maintained in an inactive conformation by Asp-Asp-Asp “safety-catch” regulatory tripeptide contained within flexible loop near the large-subunit/small-subunit junction. Removal of this “safety catch” results substantially enhanced autocatalytic maturation well increased vulnerability to proteolytic activation upstream proteases apoptotic pathway such caspase-9 granzyme B. The safety catch functions through multiple ionic interactions that...