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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 Structure–Kinetic Relationships
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-27 00:00:00 , 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-27 00:00:00 , 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
Affiliation
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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.
中文翻译：
7-Oxo-2,4,5,7-四氢-6 H-吡唑并[3,4- c ]吡啶衍生物的发现，有效，可口服和可穿透脑的受体相互作用蛋白1（RIP1）激酶抑制剂：分析动力学关系图
我们报告发现7-oxo-2,4,5,7-四氢-6 H-吡唑并[3,4- c ]吡啶衍生物作为一种新型的受体相互作用蛋白1（RIP1）激酶抑制剂。在HTS命中10与RIP1激酶的GSK2982772（6）之间的叠加研究的基础上，我们设计并合成了具有中度RIP1激酶抑制活性和P-gp介导外排的新型RIP1激酶抑制剂11。核心结构的优化和利用SBDD方法探索适当取代基的发现导致发现22，一种具有出色PK谱的高效，口服，可穿透脑的RIP1激酶抑制剂。化合物22显着抑制小鼠和人类细胞中的坏死性细胞死亡。在多发性硬化症（MS）小鼠实验性自身免疫性脑脊髓炎（EAE）模型中，口服22（10 mg / kg，bid）的剂量可减轻疾病的进展。此外，还讨论了我们新化学系列的结构动力学关系（SKR）分析。
更新日期：2018-02-27
中文翻译：
7-Oxo-2,4,5,7-四氢-6 H-吡唑并[3,4- c ]吡啶衍生物的发现，有效，可口服和可穿透脑的受体相互作用蛋白1（RIP1）激酶抑制剂：分析动力学关系图
我们报告发现7-oxo-2,4,5,7-四氢-6 H-吡唑并[3,4- c ]吡啶衍生物作为一种新型的受体相互作用蛋白1（RIP1）激酶抑制剂。在HTS命中10与RIP1激酶的GSK2982772（6）之间的叠加研究的基础上，我们设计并合成了具有中度RIP1激酶抑制活性和P-gp介导外排的新型RIP1激酶抑制剂11。核心结构的优化和利用SBDD方法探索适当取代基的发现导致发现22，一种具有出色PK谱的高效，口服，可穿透脑的RIP1激酶抑制剂。化合物22显着抑制小鼠和人类细胞中的坏死性细胞死亡。在多发性硬化症（MS）小鼠实验性自身免疫性脑脊髓炎（EAE）模型中，口服22（10 mg / kg，bid）的剂量可减轻疾病的进展。此外，还讨论了我们新化学系列的结构动力学关系（SKR）分析。
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