【行业】浮米每周文献快讯：2014年6月（四）

2014-06-23 浮米hfoom

1、Bristol-Myers Squibb的Kv1.5钾离子通道抑制剂；2、阿斯利康的Bcl-2/Bcl-xL双靶点抑制剂；3、GSK的FFA4/GPR120激动剂，研究表明FFA4/GPR120在由长链脂肪酸刺激的GLP-1分泌途径中发挥重要作用；4、GSK的HIV-1整合酶抑制剂；5和6均为阿斯利康的TRPA1拮抗剂，TRPA1离子通道与一系列感官刺激作用表现相关，已被作为治疗包括神经性和炎症性疼痛的药物靶点。Glenmar启动GRC-17536的两个临床II期试验，分别针对神经性疼痛和哮喘。Hydra/Cubist也启动了CB-189625治疗疼痛的临床I期试验。

1. Design, synthesis and evaluation of phenethylaminoheterocycles as Kv1.5 inhibitors

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3018–3022

DOI: 10.1016/j.bmcl.2014.05.035

公司/组织：Bristol-Myers Squibb

候选药物化学结构式/活性：

                               
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靶点/作用机制：Kv1.5钾离子通道抑制剂

摘要原文：

Phenethylaminoheterocycles have been prepared and assayed for inhibition of the Kv1.5 potassium ion channel as a potential approach to the treatment of atrial fibrillation. A diverse set of heterocycles were identified as potent Kv1.5 inhibitors and were advanced to pharmacodynamic evaluation based on selectivity and pharmacokinetic profile. Heterocycle optimization and template modification lead to the identification of compound 24 which demonstrated increased atrial effective refractory period in the rabbit pharmacodynamic model with mild effects on blood pressure and heart rate.

备注：

目前治疗心律失常的药物包括非选择性的离子通道阻断剂。较为安全的一个疗法是靶向心房特异性离子通道。

2. Towards the next generation of dual Bcl-2/Bcl-xL inhibitors

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3026–3033

DOI: 10.1016/j.bmcl.2014.05.036

公司/组织：阿斯利康

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靶点/作用机制：Bcl-2/Bcl-xL双靶点抑制剂

摘要原文：

Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.

备注：

                               
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3. Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120)

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3100–3103

DOI: 10.1016/j.bmcl.2014.05.012

公司/组织：GlaxoSmithKline

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靶点/作用机制：FFA4/GPR120激动剂   

摘要原文：

The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.

备注：

在治疗II型糖尿病方面，针对GLP-1取得了一定的成功。研究表明FFA4/GPR120在由长链脂肪酸刺激的GLP-1分泌途径中发挥重要作用。

4. Naphthyridinone (NTD) integrase inhibitors 4. Investigating N1 acetamide substituent effects with C3 amide groups

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3104–3107

DOI: 10.1016/j.bmcl.2014.05.011

公司/组织：GSK

候选药物化学结构式/活性：

                               
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靶点/作用机制：HIV-1整合酶抑制剂

摘要原文：

A series of N1 acetamide substituted naphthyridinone HIV-1 integrase inhibitors have been explored to understand structure–activity relationships (SAR) with various C3 amide groups. Investigations were evaluated using integrase enzyme inhibition, antiviral activity and protein binding effects to optimize the sub-structures. Lipophilicity was also incorporated to understand ligand lipophilic efficiency as a function of the structural modifications. Three representative analogs were further examined in a peripheral blood mononuclear cell (PBMC) antiviral assay as well as in vitro and in vivo drug metabolism and pharmacokinetic studies.

备注：

5.Discovery of a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine and a 1-aryloxyisoquinoline series of TRPA1 antagonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3199–3203

DOI: 10.1016/j.bmcl.2014.04.045

公司/组织：阿斯利康

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靶点/作用机制：TRPA1拮抗剂

摘要原文：

A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.

备注：

TRPA1离子通道与一系列感官刺激作用表现相关，已被作为治疗包括神经性和炎症性疼痛的药物靶点。Glenmar启动GRC-17536的两个临床II期试验，分别针对神经性疼痛和哮喘。Hydra/Cubist也启动了CB-189625治疗疼痛的临床I期试验。

6. Discovery of a series of aryl-N-(3-(alkylamino)-5-(trifluoromethyl)phenyl)benzamides as TRPA1 antagonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3204–3206

DOI: 10.1016/j.bmcl.2014.05.013

公司/组织：阿斯利康

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靶点/作用机制：TRPA1拮抗剂

摘要原文：

We describe the discovery and advancement of a novel series of TRPA1 antagonist having an aryl-N-(3-(alkylamino)-5-(trifluoromethyl)phenyl)benzamide scaffold. The physical and in vitro DMPK profiles are discussed.

备注：

(by 浮米网)

好资料，感谢分享

非常好的资料，谢谢分享。