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

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.

• Authors: 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 Geddes, Peter 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 10 Pg. 5096-5110 (05 23 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 31013427 (Publication Type: Journal Article)

Chemical References

• AGFG1 protein, human
• Enzyme Inhibitors
• Nuclear Pore Complex Proteins
• Pyrazoles
• RNA-Binding Proteins

Topics

• Animals
• Biological Availability
• Cell Line
• Chronic Disease
• Drug Design
• Encephalomyelitis, Autoimmune, Experimental (drug therapy)
• Enzyme Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Haplorhini
• High-Throughput Screening Assays
• Humans
• Mice
• Mice, Inbred C57BL
• Models, Molecular
• Multiple Sclerosis (drug therapy)
• Nuclear Pore Complex Proteins (antagonists & inhibitors)
• Pyrazoles (chemical synthesis, pharmacokinetics, pharmacology)
• RNA-Binding Proteins (antagonists & inhibitors)
• Rats
• Retinitis Pigmentosa (drug therapy)
• Structure-Activity Relationship