5932-34-3Relevant academic research and scientific papers
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
Yoshikawa, Masato,Saitoh, Morihisa,Katoh, Taisuke,Seki, Tomohiro,Bigi, Simone V.,Shimizu, Yuji,Ishii, Tsuyoshi,Okai, Takuro,Kuno, Masako,Hattori, Harumi,Watanabe, Etsuro,Saikatendu, Kumar S.,Zou, Hua,Nakakariya, Masanori,Tatamiya, Takayuki,Nakada, Yoshihisa,Yogo, Takatoshi
, p. 2384 - 2409 (2018/03/26)
We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as a novel class of receptor interacting protein 1 (RIP1) kinase inhibitors. On the basis of the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1 kinase, we designed and synthesized a novel class of RIP1 kinase inhibitor 11 possessing moderate RIP1 kinase inhibitory activity and P-gp mediated efflux. The optimization of the core structure and the exploration of appropriate substituents utilizing SBDD approach led to the discovery of 22, a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with excellent PK profiles. Compound 22 significantly suppressed necroptotic cell death both in mouse and human cells. Oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Moreover, analysis of structure-kinetic relationship (SKR) for our novel chemical series was also discussed.
