Autor: |
Stéphane Sautet, Emilie Jigorel, Nicolas Faucher, Jamel Meslamani, Lara Kathryn Leister, Pascal Grondin, Julie A. Cox, Bryan W. King, Pamela Nassau, Gemma Victoria White, Brad J. Geddes, Alain Claude-Marie Daugan, Helen H. Sun, Michael T. Ouellette, Pauline Lamoureux, Elizabeth J. Rivera, Scott B. Berger, James H. Thorpe, Philip A. Harris, J. Mosley, Susan E. Hutchinson, Frédéric Donche, John Bertin, Sandra J. Hoffman, Natalie Wellaway, Patrick M. Eidam, Paris Ward, Florent Potvain, Clark A. Sehon, Sebastien Andre Campos, Robert W. Marquis, Peter J. Gough, Mukesh K. Mahajan, Veronique Beneton, Jae U. Jeong, Michelle C. Schaeffer, John D. Lich, Allison M. Beal, Rakesh Nagilla, James Michael Woolven, Bonnie L. Hoffman, Anderson Niall Andrew, Marie-Hélène Fouchet, Deepak Bandyopadhyay, Carol A. Capriotti, Rachel D. Totoritis, Joshua N. Finger, Kishore K. Pasikanti, David D. Wisnoski, Sze-Ling Ng, Nino Campobasso, Nicolas George, Michael Reilly |
Rok vydání: |
2019 |
Předmět: |
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Zdroj: |
Journal of Medicinal Chemistry. 62:5096-5110 |
ISSN: |
1520-4804 0022-2623 |
Popis: |
RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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