浮米每周文献快讯：2015年六月（五）

浮米每周文献快讯：2015年六月（五） 作者：浮米网 来源：浮米网

• 原文标题及出处：
  

Design, Synthesis, and Structure–Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors

J. Med. Chem., 2015, 58 (12), pp 5028–5037

DOI: 10.1021/acs.jmedchem.5b00424

公司/组织：Vertex Pharmaceuticals

候选药物化学结构式/活性：

                               
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靶点/作用机制：ROCK抑制剂

摘要原文：

The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.

备注：

Rho激酶（ROCK1和ROCK2）是丝/苏氨酸激酶，磷酸化一系列胞内底物，与肌动蛋白-细胞骨架的重组相关，进而影响细胞黏附、细胞形态、细胞能动性以及平滑肌收缩。因而，ROCK与高血压、心血管疾病、青光眼、雷诺氏疾病以及勃起功能障碍相关。

• 原文标题及出处：
  

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1

J. Med. Chem., 2015, 58 (12), pp 5053–5074

DOI: 10.1021/acs.jmedchem.5b00464

公司/组织：Genentech

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靶点/作用机制：Chk1抑制剂

摘要原文：

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

备注：

丝/苏氨酸激酶ChK1在细胞周期中发挥重要作用，与细胞发生DNA损伤而滞留于G2/M期相关。肿瘤细胞或由于有p53突变，在细胞周期早期缺失了G1/S检查点调控，因而ChK1介导的检查点调控更为重要。

• 原文标题及出处：
  

Design of selective PI3Kα inhibitors starting from a promiscuous pan kinase scaffold

Bioorganic & Medicinal Chemistry Letters 25 (2015) 2679–2685

doi:10.1016/j.bmcl.2015.04.084

公司/组织：AstraZeneca

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靶点/作用机制：PI3Kα抑制剂

摘要原文：

Starting from compound 1, a potent PI3Kα inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3Kα and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Kα, with excellent kinase selectivity.

备注：

PI3K家族在与细胞增殖\存活相关的一系列细胞过程中发挥重要作用.

了解下，辛苦

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感谢分享！！

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