【行业】浮米每周文献快讯：2014年8月（二）

【行业】浮米每周文献快讯：2014年8月（二）2014-08-18 浮米hfoom

1. 2-Alkyloxazoles as potent and selective PI4KIIIβ inhibitors demonstrating inhibition of HCV replication
Bioorganic & Medicinal Chemistry Letters 24 (2014) 3714–3718
DOI: 10.1016/j.bmcl.2014.07.015
公司/组织：诺华
候选药物化学结构式/活性：

                               
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靶点/作用机制：PI4KIIIβ抑制剂
摘要原文：
Synthesis and SAR of 2-alkyloxazoles as class III phosphatidylinositol-4-kinase beta (PI4KIIIβ) inhibitors is described. These compounds demonstrate that inhibition of PI4KIIIβ leads to potent inhibition of HCV replication as observed in genotype (GT) 1a and 1b replicon and GT2a JFH1 virus assays in vitro.
备注：
PI4KIIIα和β与丙肝病毒复制有关。

2. Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase
Bioorganic & Medicinal Chemistry Letters 24 (2014) 3764–3771
DOI: 10.1016/j.bmcl.2014.06.076
公司/组织：Genentech/药明康德
候选药物化学结构式/活性：

                               
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靶点/作用机制：乳酸脱氢酶抑制剂
摘要原文：
A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50 = 1.7 μM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50 = 0.18 μM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure–activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F = 45%).
备注：

                               
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3. Optimization beyond AMG 232: Discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein–protein interaction

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3782–3785
DOI: 10.1016/j.bmcl.2014.06.073
公司/组织：Amgen
候选药物化学结构式/活性：

                               
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靶点/作用机制：MDM2–p53相互作用抑制剂
摘要原文：
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2–p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
备注：
已报道的选择性MDM2–p53相互作用抑制剂AM-8553（1） HTRF IC50 = 1.1 nM, EdU IC50 = 72 nM和AMG 232 (2) HTRF IC50 = 0.6 nM, EdU IC50 = 9.1 nM。

                               
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4. Reduction in lipophilicity improved the solubility, plasma–protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3891–3897
DOI: 10.1016/j.bmcl.2014.06.048
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：
Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma–protein unbound fraction and improvements in cellular permeability and aqueous solubility.
备注：
RORc 与多条炎症通路相关。
Genentech 已报道的RORc反向激动剂：

                               
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5. Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3898–3902
DOI: 10.1016/j.bmcl.2014.06.046
公司/组织：武田药品工业
候选药物化学结构式/活性：

                               
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靶点/作用机制：再摄取抑制剂
摘要原文：
A novel series of triple reuptake inhibitors were explored by ligand-based drug design. A cyclic structure was designed from cyclopropane derivative 5 using the core structure of reported monoamine reuptake inhibitors, leading to the formation of the 1-aryl-1,4-diazepan-2-one derivative 23j-S. Compound 23j-S was shown to act as a potent TRI with an excellent ADME-Tox profile. Oral administration of 23j-S significantly enhanced norepinephrine, dopamine, and serotonin levels in the mouse prefrontal cortex and showed significant antidepressant-like activity in tail suspension tests in mouse.
备注：
单胺转运蛋白已作为中枢神经系统治疗药物的靶点。选择性5-羟色胺再摄取单抑制剂和5-羟色胺及去甲肾上腺素再摄取双抑制剂都被作为抗抑郁药。目前许多三重再摄取抑制剂已进入抗抑郁症的临床试验，包括Amitifadine (EB-1010, formerly DOV-21,947)和 GSK372475 (NS-2359)。

(by 浮米网)

好资料，感谢分享

感谢楼主分享，及时跟进文献还是很有必要的