浮米每周文献快讯：2015年六月（四）

浮米每周文献快讯：2015年六月（四） 作者：浮米网 来源：浮米网

1. 原文标题及出处：
Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists
Bioorganic & Medicinal Chemistry Letters 25 (2015) 2907–2912
doi:10.1016/j.bmcl.2015.05.055
公司/组织：Genentech
候选药物化学结构式/活性：

                               
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靶点/作用机制：RORc反向激动剂
摘要原文：
The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORγ, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARγ, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology.
备注：
核受体视黄酸受体相关孤儿受体γ（RORγ或RORc）是IL-17以及IL-22、先天淋巴细胞的细胞因子生成的重要调节分子。而IL-17与牛皮癣、风湿性关节炎、强直性脊柱炎和葡萄膜炎相关。

2. 原文标题及出处：
Discovery of novel pyrazole-containing benzamides as potent RORγ inverse agonists
Bioorganic & Medicinal Chemistry Letters 25 (2015) 2985–2990
doi:10.1016/j.bmcl.2015.05.028
公司/组织：Biogen
候选药物化学结构式/活性：

                               
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靶点/作用机制：RORγ反向激动剂
摘要原文：
The nuclear receptor RORγ plays a central role in controlling a pro-inflammatory gene expression program in several lymphocyte lineages including TH17 cells. RORγ-dependent inflammation has been implicated in the pathogenesis of several major autoimmune diseases and thus RORγ is an attractive target for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent RORγ inverse agonists.
备注：

3. 原文标题及出处：
Discovery of biaryl carboxylamides as potent RORγ inverse agonists
Bioorganic & Medicinal Chemistry Letters 25 (2015) 2991–2997
doi:10.1016/j.bmcl.2015.05.026
公司/组织：
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靶点/作用机制：RORγ反向激动剂
摘要原文：
RORγt is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORγ activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORγ inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORγ protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORγ inverse agonists, with demonstrated oral bioavailability in rodents.
备注：

4. 原文标题及出处：
Use of molecular modeling aided design to dial out hERG liability in adenosine A2A receptor antagonists
Bioorganic & Medicinal Chemistry Letters 25 (2015) 2958–2962
doi:10.1016/j.bmcl.2015.05.036
公司/组织：默克
候选药物化学结构式/活性：

                               
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靶点/作用机制：腺苷酸受体A2A拮抗剂
摘要原文：
Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile.
备注：
腺苷酸受体A2A属于G蛋白偶联受体。腺苷酸受体A2A与多巴胺受体D2分布于基底核同一位置，但发挥相反的作用。腺苷酸受体A2A的拮抗剂是治疗帕丁森综合症的非多巴类药物。

5. 原文标题及出处：
Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors
Bioorganic & Medicinal Chemistry Letters 25 (2015) 3039–3043
doi:10.1016/j.bmcl.2015.04.098
公司/组织：BMS
候选药物化学结构式/活性：

                               
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靶点/作用机制：神经激肽1受体(NK1R)拮抗剂& 5-羟色胺转运子抑制剂
摘要原文：
Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11–84%) via dose selection
备注：
5-羟色胺选择性重摄取抑制剂以及NK1R拮抗剂都具有抗抑郁的活性。而二者还具有协同增效的作用。

谢谢分享，辛苦

感谢分享！！

感谢分享！！

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