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 HarrisNicolas FaucherNicolas GeorgePatrick M EidamBryan W KingGemma V WhiteNiall A AndersonDeepak BandyopadhyayAllison M BealVeronique BenetonScott B BergerNino CampobassoSebastien CamposCarol A CapriottiJulie A CoxAlain DauganFrederic DoncheMarie-Hélène FouchetJoshua N FingerBrad GeddesPeter J GoughPascal GrondinBonnie L HoffmanSandra J HoffmanSusan E HutchinsonJae U JeongEmilie JigorelPauline LamoureuxLara K LeisterJohn D LichMukesh K MahajanJamel MeslamaniJulie E MosleyRakesh NagillaPamela M NassauSze-Ling NgMichael T OuelletteKishore K PasikantiFlorent PotvainMichael A ReillyElizabeth J RiveraStéphane SautetMichelle C SchaefferClark A SehonHelen SunJames H ThorpeRachel D TotoritisParis WardNatalie WellawayDavid D WisnoskiJames M WoolvenJohn BertinRobert W MarquisPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- high throughput
- protein kinase
- oxidative stress
- multiple sclerosis
- endothelial cells
- amyotrophic lateral sclerosis
- rheumatoid arthritis
- clinical trial
- tyrosine kinase
- ulcerative colitis
- induced pluripotent stem cells
- mouse model
- pluripotent stem cells
- single cell
- binding protein
- interstitial lung disease
- disease activity
- ankylosing spondylitis
- amino acid
- cerebral ischemia
- idiopathic pulmonary fibrosis