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

Journal Article · · Journal of Medicinal Chemistry
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  1. GlaxoSmithKline, Collegeville, PA (United States)
  2. GlaxoSmithKline, Les Ulis Cedex (France)
  3. GlaxoSmithKline, Stevenage, Hertfordshire (United Kingdom)
+ Show Author Affiliations

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. Here, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE
OSTI ID:
1544867
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 10 Vol. 62; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (23)

Activation of Necroptosis in Multiple Sclerosis journal March 2015
RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response Syndrome journal December 2011
RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4 journal July 2016
Structural Basis of RIP1 Inhibition by Necrostatins journal March 2013
Two mouse retinal degenerations caused by missense mutations in the β-subunit of rod cGMP phosphodiesterase gene journal March 2007
Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC:  A High-Throughput Alternative to log P/log D journal June 1997
DNA-Encoded Library Screening Identifies Benzo[ b ][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors journal February 2016
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases journal February 2017
Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H -pyrazolo[3,4- c ]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure–Kinetic Relationships journal February 2018
Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis journal October 2013
TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation journal July 2012
RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury journal May 2016
A novel role for RIP1 kinase in mediating TNFα production journal June 2012
Characterization of GSK′963: a structurally distinct, potent and selective inhibitor of RIP1 kinase journal July 2015
Life after death: RIP1 and RIP3 move beyond necroptosis journal July 2016
RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis journal August 2014
RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis journal September 2014
Necroptosis and its role in inflammation journal January 2015
Identification of RIP1 kinase as a specific cellular target of necrostatins journal April 2008
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury journal May 2005
The Dual Functions of Receptor Interacting Protein 1 in Fas-Induced Hepatocyte Death During Sepsis journal January 2011
A Small Molecule Smac Mimic Potentiates TRAIL- and TNF -Mediated Cell Death journal September 2004
Cutting Edge: RIP1 Kinase Activity Is Dispensable for Normal Development but Is a Key Regulator of Inflammation in SHARPIN-Deficient Mice journal May 2014

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Anatomy
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Inhibitors
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