Receptor-interacting protein kinase 1 (RIPK1) inhibitor: a review of the patent literature (2018-present)

IntroductionRIPK1 is a critical mediator of inflammation and cell death, which is associated with extensive neurodegenerative and inflammatory diseases. Recently, RIPK1 has aroused the interests of pharmaceutical industry and research institutions.Areas coveredThis review focuses on patent literature covering small-molecule inhibitors of RIPK1 since 2018. SciFinder and PubMed databases were used for patent and literature searching.Expert opinionStudies of RIPK1 inhibitors for the necroptosis pathway have increased dramatically in recent years. To date, dozens of RIPK1 inhibitors have been reported, and several have entered clinical studies. However, the development of RIPK1 inhibitors is still at a preliminary stage. An understanding of the dosage and disease indications of RIPK1 inhibitors, rational structural optimization, and the optimal clinical setting for new structures will require feedback from further clinical trials. Recently, compared with type III inhibitors, the patents on type II inhibitors have dramatically increased. Most of them contain hybrid structures of type II/III inhibitors occupying the ATP-binding pocket and the back hydrophobic pocket of RIPK1. Patents of RIPK1 degraders were also disclosed, but the role of RIPK1 kinase- independent and dependent in promoting cell death and diseases must be considered.