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Your search keyword '"Heasley, Steven E."' showing total 11 results
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11 results on '"Heasley, Steven E."'

1. Discovery of 3-Cyano-N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist

Author

Schnute, Mark E., primary, Wennerstål, Mattias, additional, Alley, Jennifer, additional, Bengtsson, Martin, additional, Blinn, James R., additional, Bolten, Charles W., additional, Braden, Timothy, additional, Bonn, Tomas, additional, Carlsson, Bo, additional, Caspers, Nicole, additional, Chen, Ming, additional, Choi, Chulho, additional, Collis, Leon P., additional, Crouse, Kimberly, additional, Färnegårdh, Mathias, additional, Fennell, Kimberly F., additional, Fish, Susan, additional, Flick, Andrew C., additional, Goos-Nilsson, Annika, additional, Gullberg, Hjalmar, additional, Harris, Peter K., additional, Heasley, Steven E., additional, Hegen, Martin, additional, Hromockyj, Alexander E., additional, Hu, Xiao, additional, Husman, Bolette, additional, Janosik, Tomasz, additional, Jones, Peter, additional, Kaila, Neelu, additional, Kallin, Elisabet, additional, Kauppi, Björn, additional, Kiefer, James R., additional, Knafels, John, additional, Koehler, Konrad, additional, Kruger, Lars, additional, Kurumbail, Ravi G., additional, Kyne, Robert E., additional, Li, Wei, additional, Löfstedt, Joakim, additional, Long, Scott A., additional, Menard, Carol A., additional, Mente, Scot, additional, Messing, Dean, additional, Meyers, Marvin J., additional, Napierata, Lee, additional, Nöteberg, Daniel, additional, Nuhant, Philippe, additional, Pelc, Matthew J., additional, Prinsen, Michael J., additional, Rhönnstad, Patrik, additional, Backström-Rydin, Eva, additional, Sandberg, Johnny, additional, Sandström, Maria, additional, Shah, Falgun, additional, Sjöberg, Maria, additional, Sundell, Aron, additional, Taylor, Alexandria P., additional, Thorarensen, Atli, additional, Trujillo, John I., additional, Trzupek, John D., additional, Unwalla, Ray, additional, Vajdos, Felix F., additional, Weinberg, Robin A., additional, Wood, David C., additional, Xing, Li, additional, Zamaratski, Edouard, additional, Zapf, Christoph W., additional, Zhao, Yajuan, additional, Wilhelmsson, Anna, additional, and Berstein, Gabriel, additional

Published
2018
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2. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

Author

Vazquez, Michael L., primary, Kaila, Neelu, additional, Strohbach, Joseph W., additional, Trzupek, John D., additional, Brown, Matthew F., additional, Flanagan, Mark E., additional, Mitton-Fry, Mark J., additional, Johnson, Timothy A., additional, TenBrink, Ruth E., additional, Arnold, Eric P., additional, Basak, Arindrajit, additional, Heasley, Steven E., additional, Kwon, Soojin, additional, Langille, Jonathan, additional, Parikh, Mihir D., additional, Griffin, Sarah H., additional, Casavant, Jeffrey M., additional, Duclos, Brian A., additional, Fenwick, Ashley E., additional, Harris, Thomas M., additional, Han, Seungil, additional, Caspers, Nicole, additional, Dowty, Martin E., additional, Yang, Xin, additional, Banker, Mary Ellen, additional, Hegen, Martin, additional, Symanowicz, Peter T., additional, Li, Li, additional, Wang, Lu, additional, Lin, Tsung H., additional, Jussif, Jason, additional, Clark, James D., additional, Telliez, Jean-Baptiste, additional, Robinson, Ralph P., additional, and Unwalla, Ray, additional

Published
2018
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3. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases

Author

Vazquez, Michael L., Kaila, Neelu, Strohbach, Joseph W., Trzupek, John D., Brown, Matthew F., Flanagan, Mark E., Mitton-Fry, Mark J., Johnson, Timothy A., TenBrink, Ruth E., Arnold, Eric P., Basak, Arindrajit, Heasley, Steven E., Kwon, Soojin, Langille, Jonathan, Parikh, Mihir D., Griffin, Sarah H., Casavant, Jeffrey M., Duclos, Brian A., Fenwick, Ashley E., Harris, Thomas M., Han, Seungil, Caspers, Nicole, Dowty, Martin E., Yang, Xin, Banker, Mary Ellen, Hegen, Martin, Symanowicz, Peter T., Li, Li, Wang, Lu, Lin, Tsung H., Jussif, Jason, Clark, James D., Telliez, Jean-Baptiste, Robinson, Ralph P., and Unwalla, Ray

Abstract

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.

Published
2024
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4. Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: Use of a conformation-based hypothesis to facilitate compound design

Author

Walker, Daniel P., Arhancet, Graciela B., Lu, Hwang-Fun, Heasley, Steven E., Metz, Sue, Kablaoui, Natasha M., Franco, Francisco M., Hanau, Cathleen E., Scholten, Jeffrey A., Springer, John R., Fobian, Yvette M., Carter, Jeffrey S., Xing, Li, Yang, Shengtian, Shaffer, Alexander F., Jerome, Gina M., Baratta, Michael T., Moore, William M., and Vazquez, Michael L.

Published
2013
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6. Acidic triazoles as soluble guanylate cyclase stimulators

Author

Roberts, Lee R., Bradley, Paul A., Bunnage, Mark E., England, Katherine S., Fairman, David, Fobian, Yvette M., Fox, David N.A., Gymer, Geoff E., Heasley, Steven E., Molette, Jerome, Smith, Graham L., Schmidt, Michelle A., Tones, Michael A., and Dack, Kevin N.

Published
2011
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8. Design, Synthesis, and Biological Evaluation of 3-[4-(2-Hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a Potent, Orally Active, Brain Penetrant Inhibitor of Phosphodiesterase 5 (PDE5)

Author

Hughes, Robert O., primary, Rogier, D. Joseph, additional, Jacobsen, E. Jon, additional, Walker, John K., additional, MacInnes, Alan, additional, Bond, Brian R., additional, Zhang, Lena L., additional, Yu, Ying, additional, Zheng, Yi, additional, Rumsey, Jeanne M., additional, Walgren, Jennie L., additional, Curtiss, Sandra W., additional, Fobian, Yvette M., additional, Heasley, Steven E., additional, Cubbage, Jerry W., additional, Moon, Joseph B., additional, Brown, David L., additional, Acker, Brad A., additional, Maddux, Todd M., additional, Tollefson, Mike B., additional, Mischke, Brent V., additional, Owen, Dafydd R., additional, Freskos, John N., additional, Molyneaux, John M., additional, Benson, Alan G., additional, and Blevis-Bal, Rhadika M., additional

Published
2010
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9. Solvent and in situ catalyst preparation impacts upon Noyori reductions of aryl-chloromethyl ketones: application to syntheses of chiral 2-amino-1-aryl-ethanols

Author

Tanis, Steven P., primary, Evans, Bruce R., additional, Nieman, James A., additional, Parker, Timothy T., additional, Taylor, Wendy D., additional, Heasley, Steven E., additional, Herrinton, Paul M., additional, Perrault, William R., additional, Hohler, Richard A., additional, Dolak, Lester A., additional, Hester, Matthew R., additional, and Seest, Eric P., additional

Published
2006
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10. A Practical Synthesis of [(1S,3S)-3-Aminocyclohexyl]methanol and 2-[(1S,3S)-3-Aminocyclohexyl]propan-2-ol, Useful Intermediates for the Preparation of Novel mPGES-1 Inhibitors.

Author

Walker, Daniel P., Heasley, Steven E., MacInnes, Allison, Anjeh, Tizah, Hwang-Fun Lu, Fobian, Yvette M., Collins, Joe T., Vazquez, Michael L., and Mao, Michael K.

Subjects
*CHEMICAL synthesis, *METHANOL, *AMINO alcohols, *CARBOCYCLIC acids, *CHIRALITY, *ANTI-inflammatory agents
Abstract

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. During the course of studies aimed at the identification of a suitable mPGES-1 inhibitor for clinical development, a need arose for preparing enantiomerically enriched amino alcohols (S,S)-2 and (S,S)-3. Described herein, a concise synthesis of (S,S)-2 and (S,S)-3 has been developed wherein both amino alcohols are derived from a commercially available, low-cost starting material. [ABSTRACT FROM AUTHOR]

Published
2011
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11. Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist.

Author

Schnute ME, Wennerstål M, Alley J, Bengtsson M, Blinn JR, Bolten CW, Braden T, Bonn T, Carlsson B, Caspers N, Chen M, Choi C, Collis LP, Crouse K, Färnegårdh M, Fennell KF, Fish S, Flick AC, Goos-Nilsson A, Gullberg H, Harris PK, Heasley SE, Hegen M, Hromockyj AE, Hu X, Husman B, Janosik T, Jones P, Kaila N, Kallin E, Kauppi B, Kiefer JR, Knafels J, Koehler K, Kruger L, Kurumbail RG, Kyne RE Jr, Li W, Löfstedt J, Long SA, Menard CA, Mente S, Messing D, Meyers MJ, Napierata L, Nöteberg D, Nuhant P, Pelc MJ, Prinsen MJ, Rhönnstad P, Backström-Rydin E, Sandberg J, Sandström M, Shah F, Sjöberg M, Sundell A, Taylor AP, Thorarensen A, Trujillo JI, Trzupek JD, Unwalla R, Vajdos FF, Weinberg RA, Wood DC, Xing L, Zamaratski E, Zapf CW, Zhao Y, Wilhelmsson A, and Berstein G

Subjects
Administration, Oral, Animals, Biological Availability, Drug Evaluation, Preclinical, Humans, Mice, Pyridines pharmacokinetics, Th17 Cells drug effects, Th17 Cells metabolism, Drug Design, Drug Inverse Agonism, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Pyridines administration & dosage, Pyridines pharmacology
Abstract

The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

Published
2018
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