Masato Yoshikawa; Morihisa Saitoh; Taisuke Katoh; Tomohiro Seki; Simone V. Bigi; Yuji Shimizu; Tsuyoshi Ishii; Takuro Okai; Masako Kuno; Harumi Hattori; Etsuro Watanabe; Kumar S. Saikatendu; Hua Zou; Masanori Nakakariya; Takayuki Tatamiya; Yoshihisa Nakada; Takatoshi Yogo
J. Med. Chem., 2018, 61, 6, 2384-2409
https://doi.org/10.1021/acs.jmedchem.7b01647

Abstract

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.