浮米每周文献快讯：2014年11月（一）

浮米每周文献快讯：2014年11月（一）                                                                       作者：浮米网 来源：浮米网  2014-11-05

1. Design, synthesis and evaluation of [3H]PF-7191, a highly specific nociceptin opioid peptide (NOP) receptor radiotracer for in vivo receptor occupancy (RO) studies
Bioorganic & Medicinal Chemistry Letters 24 (2014) 5219–5223
DOI: 10.1016/j.bmcl.2014.09.069
公司/组织：辉瑞
候选药物化学结构式/活性：

                               
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靶点/作用机制：痛敏肽阿片类多肽（NOP）受体放射性示踪物
摘要原文：
Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6′-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1′-isochroman]-8-yl)propyl)-N-[3H]-methylacetamide {[3H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki = 0.1 nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (Cb,u/Cp,u = 0.29). Subsequent characterization of [3H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [3H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose–responsive manner. This overall favorable profile indicated that [3H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species.
备注：
研发选择性NOP拮抗剂可用于治疗抑郁、焦躁、帕金森症和糖尿病。而这篇研究针对NOP受体放射性示踪物，可以用于临床候选药物的选择。

2. Discovery of a novel pyrazole series of group X secreted phospholipase A2 inhibitor (sPLA2X) via fragment based virtual screening
Bioorganic & Medicinal Chemistry Letters 24 (2014) 5251–5255
DOI: 10.1016/j.bmcl.2014.09.058
公司/组织：阿斯利康
候选药物化学结构式/活性：

                               
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靶点/作用机制：sPLA2X抑制剂
摘要原文：
The discovery of potent novel pyrazole containing group X secreted phospholipase A2 inhibitors via structure based virtual screening is reported. Docking was applied on a large set of in-house fragment collection and pharmacophore feature matching was used to filter docking poses. The selected virtual screening hits was run in NMR screening, a potent pyrazole containing fragment hit was identified and confirmed by its complex X-ray structure and the following biochemical assay result. Expansion on the fragment hit has led to further improvement of potency while maintaining high ligand efficiency, thus supporting the further development of this chemical series.
备注：
本研究利用基于片段的虚拟筛选，流程图如下

                               
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3. Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt
Bioorganic & Medicinal Chemistry Letters 24 (2014) 5265–5267
DOI: 10.1016/j.bmcl.2014.09.053
公司/组织：Phenex Pharmaceuticals AG
候选药物化学结构式/活性：

                               
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靶点/作用机制：视黄酸相关孤儿受体（ROR）反向激动剂
摘要原文：
Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) is a key transcription factor for the development of Th17 cells. Inhibiting RORγt activity is thought to be beneficial in targeting a variety of inflammatory and autoimmune disorders. Recently N-(5-(arylcarbonyl)thiazol-2-yl)amides were described as RORγt antagonists with in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) via oral administration. So far no selective small molecule ligands have been revealed for RORβ. We show, that one compound of this class, namely N-[5-(2-chloro-benzoyl)-4-(3-chlorophenyl)-thiazol-2-yl]-2-(4-ethanesulfonyl-phenyl)-acetamide (4) is a potent dual inverse agonist towards RORγt and RORβ devoid of activity to 18 other human nuclear receptors and thus can serve as chemical probe to deepen our understanding about RORβ and its biology.
备注：
ROR属于转录因子，每个亚型都有不同的组织分布。

已知非选择性RORβ配体结构：

                               
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(by 浮米网)

谢谢分享，辛苦