2. Academic Validation
  3. 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

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

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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