浮米每周文献快讯：2015年04月（三）

前沿        作者：浮米网 来源：浮米网  2015-04-20 0评论

1. 原文标题及出处：

Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2)

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1831–1835

doi:10.1016/j.bmcl.2015.03.044

公司/组织：Merck

候选药物化学结构式/活性：

                               
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靶点/作用机制：广谱抗菌药；细菌拓扑异构酶抑制剂

摘要原文：

Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 μM). In general, lower log D attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described.

备注：

细菌拓扑异构酶抑制剂是新型的抗菌药，有望克服目前的耐药性问题。这类抑制剂结合在DNA-拓扑异构酶II复合物的不同结合位点，因此，交叉耐药性能被避免。拓扑异构酶抑制剂从结构上讲通常包括三个部分：一个8元的linker，其7-位置有碱性氮；左手位双环芳杂环；右手位芳杂环。

2. 原文标题及出处：

Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine inhibitors of interleukin-1 receptor-associated kinase 4

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1836–1841

doi:10.1016/j.bmcl.2015.03.043

公司/组织：Merck

候选药物化学结构式/活性：

                               
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靶点/作用机制：白介素受体相关激酶4(IRAK4)抑制剂

摘要原文：

Interleukin receptor-associated kinase 4 (IRAK4) is a critical element of the Toll-like/interleukin-1 receptor inflammation signaling pathway. A screening campaign identified a novel diaminopyrimidine hit that exhibits weak IRAK4 inhibitory activity and a ligand efficiency of 0.25. Hit-to-lead activities were conducted through independent SAR studies of each of the four pyrimidine substituents. Optimal activity was observed upon removal of the pyrimidine C-4 chloro substituent. The intact C-6 carboribose is required for IRAK4 inhibition. Numerous heteroaryls were tolerated at the C-5 position, with azabenzothiazoles conferring the best activities. Aminoheteroaryls were preferred at the C-2 position. These studies led to the discovery of inhibitors 35, 36, and 38 that exhibit nanomolar inhibition of IRAK4, improved ligand efficiencies, and modest kinase selectivities.

备注：

目前许多针对慢性炎症疾病的药物以TNFα为靶点，这类药需要以注射方式进入血液系统从而到达靶点，并且费用较高。可口服的治疗慢性炎症的药物具有更好的优势，而IRAK4就是一个有效靶点。

3. 原文标题及出处：

Elimination of a cholecystokinin receptor agonist ‘trigger’ in an effort to develop positive allosteric modulators without intrinsic agonist activity

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1849–1855

doi:10.1016/j.bmcl.2015.03.051

公司/组织：GSK

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靶点/作用机制：胆囊收缩素受体（CCK1R）激动剂

摘要原文：

Cholecystokinin (CCK) acts at the type 1 cholecystokinin receptor (CCK1R) to elicit satiety and is a well-established drug target for obesity. To date, small molecule agonists have been developed, but have failed to demonstrate adequate efficacy in clinical trials, and concerns about side effects and potential toxicity have limited further development of full agonists. The use of positive allosteric modulators (PAMs) without intrinsic agonist activity that are active only for a brief period of time after a meal might represent a safer alternative. Here, we propose a possible novel strategy to develop such compounds by modifying the agonist ‘trigger’ of an existing small molecule agonist. We have studied analogues of the 1,5-benzodiazepine agonist, GI181771X, in which the N1-isopropyl agonist ‘trigger’ was modified. While agonist activity was greatly reduced in these compounds, they acted as negative, rather than positive modulators. The parent drug was also found to exhibit no positive modulation of CCK action. Receptor structure–activity relationship studies demonstrated that the mode of docking these derivatives was distinct from that of the parent compound, perhaps explaining their action as negative allosteric modulators. We conclude that this outcome is likely characteristic of the parental agonist, and that this strategy may be more successfully utilized with a parental ago-PAM, possessing intrinsic positive modulatory activity.

备注：

各大制药公司研发CCK1R激动剂作为治疗肥胖的药物，但这些药物往往夭折于临床试验阶段。此外，CCK1R激动剂的副作用有可能包括恶心、腹部绞痛、 腹泻。而慢性剂量的全激动剂还可能与胰腺癌有关。

4. 原文标题及出处：

Discovery of new acylaminopyridines as GSK-3 inhibitors by a structure guided in-depth exploration of chemical space around a pyrrolopyridinone core

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1856–1863

doi:10.1016/j.bmcl.2015.03.046

公司/组织：Bristol-Myers Squibb

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靶点/作用机制：GSK-3抑制剂

摘要原文：

Glycogen synthase kinase-3 (GSK-3) has been proposed to play a crucial role in the pathogenesis of many diseases including cancer, stroke, bipolar disorders, diabetes and neurodegenerative diseases. GSK-3 inhibition has been a major area of pharmaceutical interest over the last two decades. A plethora of reports appeared recently on selective inhibitors and their co-crystal structures in GSK-3β. We identified several series of promising new GSK-3β inhibitors from a coherent design around a pyrrolopyridinone core structure. A systematic exploration of the chemical space around the central spacer led to potent single digit and sub-nanomolar GSK-3β inhibitors. When dosed orally in a transgenic mouse model of Alzheimer’s disease (AD), an exemplary compound showed significant lowering of Tau phosphorylation at one of the GSK-3 phosphorylating sites, Ser396. X-ray crystallography greatly aided in validating the binding hypotheses.

备注：

糖原合成酶激酶3(GSK-3)是丝/苏氨酸激酶，与一系列疾病相关，包括糖尿病、癌症、阿尔兹海默病、情绪失调、中风等。

5. 原文标题及出处：

Discovery of 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide analogs as new RORC modulators

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1892–1895

doi:10.1016/j.bmcl.2015.03.042

公司/组织：Boehringer Ingelheim Pharmaceuticals

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靶点/作用机制：视黄素孤儿受体γ（RORC）调节剂

摘要原文：

Structure-based and pharmacophore-based virtual screening in combination with combinatorial chemistry and X-ray crystallography led to the discovery of a new class of benzothiadiazole dioxide analogs with functional activity as RORC inverse agonists. The early RORC SAR compound 14 exhibited RORC inhibition in a cell based reporter gene assay of 5.7 μM and bound to RORC with an affinity of 1.6 μM in a fluorescence polarization assay displacing a ligand binding site probe. Crystallography confirmed the binding mode of the compound in the ligand binding domain displaying the engagement of a novel sub pocket close to Ser404. Subsequent optimization yielded compounds with enhanced RORC inverse agonist activity. The most active compound 19 showed an IC50 of 440 nM in a human PBMC assay.

备注：

致病性T辅助细胞（Th17）与多种自身免疫疾病相关，包括牛皮癣、风湿性关节炎以及炎症性肠病。利用小分子抑制RORC是抑制Th17相关疾病的有效途径。

6. 原文标题及出处：

BMS-871: A novel orally active pan-Notch inhibitor as an anticancer agent

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1905–1909

doi:10.1016/j.bmcl.2015.03.038

公司/组织：Bristol-Myers Squibb

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靶点/作用机制：Notch抑制剂

摘要原文：

This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.

备注：

Notch信号通路调节细胞分化、发展和干细胞维持。该通路的失调与多种实体瘤有关。