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

  • J Med Chem. 2018 Mar 22;61(6):2384-2409. doi: 10.1021/acs.jmedchem.7b01647.
Masato Yoshikawa  1 ,  Morihisa Saitoh  1 ,  Taisuke Katoh  1 ,  Tomohiro Seki  1 ,  Simone V Bigi  2 ,  Yuji Shimizu  1 ,  Tsuyoshi Ishii  1 ,  Takuro Okai  1 ,  Masako Kuno  1 ,  Harumi Hattori  1 ,  Etsuro Watanabe  1 ,  Kumar S Saikatendu  2 ,  Hua Zou  2 ,  Masanori Nakakariya  1 ,  Takayuki Tatamiya  1 ,  Yoshihisa Nakada  1 ,  Takatoshi Yogo  1
Affiliations
  • 1. Research , Takeda Pharmaceutical Company Limited , 26-1 Muraoka-Higashi 2-chome , Fujisawa , Kanagawa 251-8555 , Japan.
  • 2. Takeda Pharmaceuticals , 10410 Science Center Drive , San Diego , California 92121 , United States.
PMID: 29485864 DOI: 10.1021/acs.jmedchem.7b01647
Abstract

We report the discovery of 7-oxo-2,4,5,7-tetrahydro-6 H-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.

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