7 results on '"Coate, Heather R."'
Search Results
2. Identification of small-molecule protein–protein interaction inhibitors for NKG2D
- Author
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Thompson, Aaron A., primary, Harbut, Michael B., additional, Kung, Pei-Pei, additional, Karpowich, Nathan K., additional, Branson, Jeffrey D., additional, Grant, Joanna C., additional, Hagan, Deborah, additional, Pascual, Heather A., additional, Bai, Guoyun, additional, Zavareh, Reza Beheshti, additional, Coate, Heather R., additional, Collins, Bernard C., additional, Côte, Marjorie, additional, Gelin, Christine F., additional, Damm-Ganamet, Kelly L., additional, Gholami, Hadi, additional, Huff, Adam R., additional, Limon, Luis, additional, Lumb, Kevin J., additional, Mak, Puiying A., additional, Nakafuku, Kohki M., additional, Price, Edmund V., additional, Shih, Amy Y., additional, Tootoonchi, Mandana, additional, Vellore, Nadeem A., additional, Wang, Jocelyn, additional, Wei, Na, additional, Ziff, Jeannie, additional, Berger, Scott B., additional, Edwards, James P., additional, Gardet, Agnès, additional, Sun, Siquan, additional, Towne, Jennifer E., additional, Venable, Jennifer D., additional, Shi, Zhicai, additional, Venkatesan, Hariharan, additional, Rives, Marie-Laure, additional, Sharma, Sujata, additional, Shireman, Brock T., additional, and Allen, Samantha J., additional
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- 2023
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- View/download PDF
3. Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793
- Author
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Anne E. Fitzgerald, Tatiana Koudriakova, Kevin J. Coe, Anthony Ndifor, Cathy Preville, Christine Dugovic, Neelakandha S. Mani, Nicholas I. Carruthers, Michele C. Rizzolio, Timothy W. Lovenberg, Brock T. Shireman, Diane Nepomuceno, Coate Heather R, Daniel J. Pippel, Brian Lord, Allison Brett Douglas, Curt A. Dvorak, and Pascal Bonaventure
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010405 organic chemistry ,Chemistry ,Sleep wake ,digestive, oral, and skin physiology ,Organic Chemistry ,Antagonist ,Neuropeptide ,Pharmacology ,01 natural sciences ,Biochemistry ,Orexin receptor ,0104 chemical sciences ,Orexin ,010404 medicinal & biomolecular chemistry ,nervous system ,mental disorders ,Drug Discovery ,Receptor ,Mode of action ,hormones, hormone substitutes, and hormone antagonists ,psychological phenomena and processes - Abstract
[Image: see text] The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.
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- 2020
4. Novel 2-phenylquinolin-7-yl-derived imidazo[1,5- a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors
- Author
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Mulvihill, Mark J., Ji, Qun-Sheng, Coate, Heather R., Cooke, Andrew, Dong, Hanqing, Feng, Lixin, Foreman, Kenneth, Rosenfeld-Franklin, Maryland, Honda, Ayako, Mak, Gilda, Mulvihill, Kristen M., Nigro, Anthony I., O’Connor, Matthew, Pirrit, Caroline, Steinig, Arno G., Siu, Kam, Stolz, Kathryn M., Sun, Yingchuan, Tavares, Paula A.R., Yao, Yan, and Gibson, Neil W.
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- 2008
- Full Text
- View/download PDF
5. Pharmacology of JNJ-28583113: A novel TRPM2 antagonist
- Author
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Nicholas I. Carruthers, Lawrence Fourgeaud, Ning Qin, Sunil Sahdeo, Curt A. Dvorak, Anindya Bhattacharya, Brian Lord, Qi Wang, Natalie Taylor, Alan D. Wickenden, Reinhold Penner, Coate Heather R, John Starkus, Yingbo He, Timothy W. Lovenberg, and Malika Faouzi
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0301 basic medicine ,Male ,medicine.medical_treatment ,TRPM Cation Channels ,Pharmacology ,medicine.disease_cause ,03 medical and health sciences ,Transient receptor potential channel ,Mice ,0302 clinical medicine ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,TRPM2 ,Microglia ,Chemistry ,Antagonist ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,HEK293 Cells ,Pyrazoles ,030217 neurology & neurosurgery ,Intracellular ,Oxidative stress ,HeLa Cells - Abstract
Transient receptor potential melastatin type 2 (TRPM2) is a cation channel activated by free intracellular ADP-ribose and reactive oxygen species. TRPM2 signaling has been linked to the pathophysiology of CNS disorders such as neuropathic pain, bipolar disorder and Alzheimer's disease. In this manuscript, we describe the discovery of JNJ-28583113, a potent brain penetrant TRPM2 antagonist. Ca2+ flux assays in cells overexpressing TRPM2 and electrophysiological recordings were used to test the pharmacology of JNJ-28583113. JNJ-28583113 was assayed in vitro on GSK-3 phosphorylation levels, cell death, cytokine release in microglia and unbiased morphological phenotypic analysis. Finally, we dosed animals to evaluate its pharmacokinetic properties. Our results showed that JNJ-28583113 is a potent (126 ± 0.5 nM) TRPM2 antagonist. Blocking TRPM2 caused phosphorylation of GSK3α and β subunits. JNJ-28583113 also protected cells from oxidative stress induced cell death as well as morphological changes induced by non-cytotoxic concentrations of H2O2. In addition, inhibiting TRPM2 blunted cytokine release in response to pro-inflammatory stimuli in microglia. Lastly, we showed that JNJ-28583113 was brain penetrant but not suitable for systemic dosing as it was rapidly metabolized in vivo. While the in-vitro pharmacology of JNJ-28583113 is the best in class, its in-vivo properties would need optimization to assist in further probing key roles of TRPM2 in CNS pathophysiology.
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- 2018
6. Identification and SAR of Glycine Benzamides as Potent Agonists for the GPR139 Receptor
- Author
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Chester Kuei, Changlu Liu, Curt A. Dvorak, Michelle Wennerholm, Timothy W. Lovenberg, Pascal Bonaventure, Coate Heather R, David Woody, Diane Nepomuceno, Nicholas I. Carruthers, and Brian Lord
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Agonist ,Stereochemistry ,medicine.drug_class ,High-throughput screening ,Organic Chemistry ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Glycine ,medicine ,Receptor ,Benzamide ,EC50 - Abstract
A focused high throughput screening for GPR139 was completed for a select 100K compounds, and new agonist leads were identified. Subsequent analysis and structure–activity relationship studies identified (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl)benzamide 7c as a potent and selective agonist of hGPR139 with an EC50 = 16 nM. The compound was found to cross the blood–brain barrier and have good drug-like properties amenable for oral dosing in rat.
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- 2015
7. GPR139, an Orphan Receptor Highly Enriched in the Habenula and Septum, Is Activated by the Essential Amino Acids L-Tryptophan and L-Phenylalanine
- Author
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Jiejun Wu, Nicholas I. Carruthers, Anthony Harrington, William A. Eckert, Grace Lee, Coate Heather R, Changlu Liu, Timothy W. Lovenberg, Steven W. Sutton, Victory Joseph, Chester Kuei, Sujin Yun, Diane Nepomuceno, Xiang Yao, Lynn Yieh, Qingqin Li, Christine Dugovic, Pascal Bonaventure, and Curt A. Dvorak
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Agonist ,Male ,medicine.drug_class ,Phenylalanine ,Molecular Sequence Data ,Guanosine ,Nerve Tissue Proteins ,Biology ,Receptors, G-Protein-Coupled ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Peptide sequence ,Pharmacology ,Orphan receptor ,chemistry.chemical_classification ,Habenula ,Kinase ,Tryptophan ,Amino acid ,Rats ,HEK293 Cells ,chemistry ,Biochemistry ,COS Cells ,Molecular Medicine ,Septum of Brain - Abstract
GPR139 is an orphan G-protein-coupled receptor expressed in the central nervous system. To identify its physiologic ligand, we measured GPR139 receptor activity from recombinant cells after treatment with amino acids, orphan ligands, serum, and tissue extracts. GPR139 activity was measured using guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding, calcium mobilization, and extracellular signal-regulated kinases phosphorylation assays. Amino acids L-tryptophan (L-Trp) and L-phenylalanine (L-Phe) activated GPR139, with EC50 values in the 30- to 300-μM range, consistent with the physiologic concentrations of L-Trp and L-Phe in tissues. Chromatography of rat brain, rat serum, and human serum extracts revealed two peaks of GPR139 activity, which corresponded to the elution peaks of L-Trp and L-Phe. With the purpose of identifying novel tools to study GPR139 function, a high-throughput screening campaign led to the identification of a selective small-molecule agonist [JNJ-63533054, (S)-3-chloro-N-(2-oxo-2-((1-phenylethyl)amino)ethyl) benzamide]. The tritium-labeled JNJ-63533054 bound to cell membranes expressing GPR139 and could be specifically displaced by L-Trp and L-Phe. Sequence alignment revealed that GPR139 is highly conserved across species, and RNA sequencing studies of rat and human tissues indicated its exclusive expression in the brain and pituitary gland. Immunohistochemical analysis showed specific expression of the receptor in circumventricular regions of the habenula and septum in mice. Together, these findings suggest that L-Trp and L-Phe are candidate physiologic ligands for GPR139, and we hypothesize that this receptor may act as a sensor to detect dynamic changes of L-Trp and L-Phe in the brain.
- Published
- 2015
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