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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

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, etc.

J Med Chem. 2018 Mar 22;61(6):2384-2409.

PMID: 29485864

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42412571	BID from mouse			Price

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