Discovery of 7‑Oxo-2,4,5,7-tetrahydro‑6H‑pyrazolo[3,4‑c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of…

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

We report herein the discovery and optimization of 7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine derivatives as a novel class of brain-penetrating receptor interacting protein 1 (RIP1) kinase inhibitors. Based on the overlay study between HTS hit 10 and GSK2982772 (6) in RIP1, we identified 4-oxo-6,7-dihydro-1H-imidazo[4,5-c]pyridine derivative 11, possessing moderate RIP1 inhibitory activity and P-gp mediated efflux. The optimization of the core structure, 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. Furthermore, oral administration of 22 (10 mg/kg, bid) attenuated disease progression in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). We also analyzed structure-kinetic relationship (SKR) for our novel chemical series and discussed the importance of evaluating drug-target residence time for lead optimization.