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Your search keyword '"Carol A. Capriotti"' showing total 3 results
Start Over Author "Carol A. Capriotti" Journal acs medicinal chemistry letters
3 results on '"Carol A. Capriotti"'

1. Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel

Author

Elizabeth J. Rivera, Brian Donovan, Ami S. Lakdawala, Nikolay V. Plotnikov, Xiaoyang Dong, Barry S. Brown, Robert Singhaus, Khuram W. Chaudhary, Rachel D. Totoritis, Adam Kenneth Charnley, Michael Reilly, Terry Vincent Hughes, Joseph J. Romano, Pamela A. Haile, Robert W. Marquis, Michael Jonathan Bury, John F. Mehlmann, Gren Z. Wang, Rakesh Nagilla, Bartholomew J. Votta, Barbara A. Swift, Linda N. Casillas, Demartino Michael P, Peter J. Gough, Mukesh K. Mahajan, Carol A. Capriotti, Biva M. Desai, Scott B. Berger, Carol LePage, Helen H. Sun, David B. Lipshutz, John Bertin, Máire A. Convery, Chaya Duraiswami, and Michael T. Ouellette

Subjects
biology, Kinase, Organic Chemistry, Quinoline, hERG, Pharmacology, Biochemistry, chemistry.chemical_compound, Therapeutic index, chemistry, Drug Discovery, biology.protein, Identification (biology), Ion channel
Published
2020
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2. Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel

Author

Rachel D. Totoritis, Robert Singhaus, Brian Donovan, Nikolay V. Plotnikov, John F. Mehlmann, Terry Vincent Hughes, Michael Jonathan Bury, Pamela A. Haile, Khuram W. Chaudhary, Gren Z. Wang, Peter J. Gough, Biva M. Desai, Michael T. Ouellette, Michael Reilly, Mukesh K. Mahajan, Barry S. Brown, Scott B. Berger, Xiaoyang Dong, Carol A. Capriotti, Carol LePage, Bartholomew J. Votta, Helen H. Sun, David B. Lipshutz, John Bertin, Joseph J. Romano, Adam Kenneth Charnley, Ami S. Lakdawala, Robert W. Marquis, Barbara A. Swift, Rakesh Nagilla, Máire A. Convery, Demartino Michael P, Elizabeth J. Rivera, and Linda N. Casillas

Subjects
0301 basic medicine, biology, 010405 organic chemistry, Chemistry, Kinase, Organic Chemistry, hERG, Pharmacology, 01 natural sciences, Biochemistry, 0104 chemical sciences, Biological pathway, 03 medical and health sciences, 030104 developmental biology, Therapeutic index, In vivo, Drug Discovery, biology.protein, IC50, Ex vivo, Ion channel
Abstract

[Image: see text] RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC(50) = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC(50) = 10 nM) with reduced hERG activity (14 μM).

Published
2018

3. Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis

Author

Kirsten M. Kahler, Philip A. Harris, Paris Ward, Michael T. Ouellette, Sandra J. Hoffman, Lauren Dare, Peter J. Gough, Helen H. Sun, Carol A. Capriotti, Michelle C. Schaeffer, Christina S. Pao, Robert T. Nolte, Joshua N. Finger, Nino Campobasso, Ruth Lehr, Angela Smallwood, Deepak Bandyopadhyay, Rachel D. Totoritis, Robert W. Marquis, John D. Lich, Rakesh Nagilla, Scott B. Berger, Barbara A. Swift, John Bertin, and Julie A. Cox

Subjects
Pyrimidine, Kinase, business.industry, Necroptosis, Organic Chemistry, Pharmacology, Hypothermia, Biochemistry, Small molecule, chemistry.chemical_compound, chemistry, Drug Discovery, medicine, Transferase, Tumor necrosis factor alpha, medicine.symptom, business
Abstract

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.

Published
2013

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