当前位置: X-MOL 学术Bioorg. Med. Chem. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Design, synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-β (TGF-β) type I receptor inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-06-10 , DOI: 10.1016/j.bmcl.2020.127339
Bin Tan 1 , Xiaomeng Zhang 2 , Xu Quan 3 , Guochuang Zheng 3 , Xue Li 3 , Liwen Zhao 3 , Wei Li 2 , Bo Li 4
Affiliation  

TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6%. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-βR1 inhibitor.



中文翻译:

新型4-(((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶-2-基)氨基衍生物的设计,合成及生物活性评估有效的转化生长因子-β(TGF-β)I型受体抑制剂。

TGF-βI型受体(也称为激活素样激酶5或ALK5)在纤维化疾病的发展以及肿瘤的侵袭和转移中也起着至关重要的作用。靶向ALK5的小抑制剂的开发已被证实是纤维化疾病和癌症的潜在治疗策略。在这里,我们开发了各种作为ALK5抑制剂的4-((1-环丙基-3-(四氢-2 H-吡喃-4-基)-1 H-吡唑-4-基)氧基)吡啶-2-基)氨基衍生物。优化导致了有效和选择性ALK5抑制剂12r的鉴定。化合物12r在体外体内均表现出强大的抑制活性和药代动力学研究显示,口服生物利用度为57.6%。因此,化合物12r可以作为ALK5TGF-βR1抑制剂提供新的治疗选择。

更新日期:2020-06-10
down
wechat
bug