Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase

Philip A. Harris, Nicolas Faucher, Nicolas George, Patrick M. Eidam, Bryan W. King, Gemma V. White, Niall A. Anderson, Deepak Bandyopadhyay, Allison M. Beal, Veronique Beneton, Scott B. Berger, Nino Campobasso, Sebastien Campos, Carol A. Capriotti, Julie A. Cox, Alain Daugan, Frederic Donche, Marie Hélène Fouchet, Joshua N. Finger, Brad GeddesPeter J. Gough, Pascal Grondin, Bonnie L. Hoffman, Sandra J. Hoffman, Susan E. Hutchinson, Jae U. Jeong, Emilie Jigorel, Pauline Lamoureux, Lara K. Leister, John D. Lich, Mukesh K. Mahajan, Jamel Meslamani, Julie E. Mosley, Rakesh Nagilla, Pamela M. Nassau, Sze Ling Ng, Michael T. Ouellette, Kishore K. Pasikanti, Florent Potvain, Michael A. Reilly, Elizabeth J. Rivera, Stéphane Sautet, Michelle C. Schaeffer, Clark A. Sehon, Helen Sun, James H. Thorpe, Rachel D. Totoritis, Paris Ward, Natalie Wellaway, David D. Wisnoski, James M. Woolven, John Bertin, Robert W. Marquis

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26 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)5096-5110
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number10
DOIs
StatePublished - 23 May 2019
Externally publishedYes

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