浮米每周文献快讯：2015年02月(一)

浮米每周文献快讯：2015年02月(一) 作者：浮米网 来源：浮米网  2015-02-02

• 原文标题及出处：
  

Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer’s disease

Bioorganic & Medicinal Chemistry Letters 25 (2015) 767–774

doi:10.1016/j.bmcl.2014.12.092

公司/组织：Amgen

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靶点/作用机制：β-分泌酶抑制剂

摘要原文：

The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer’s disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.

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• 原文标题及出处：
  

Discovery of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines as potent PIM inhibitors

Bioorganic & Medicinal Chemistry Letters 25 (2015) 775–780

doi:10.1016/j.bmcl.2014.12.091

公司/组织：Amgen

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靶点/作用机制：PIM抑制剂

摘要原文：

PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.

备注：

PIM激酶属于CAMK家族，是丝/苏氨酸激酶。PIM激酶家族在各类肿瘤中高表达,并对肿瘤的发生发展起着重要的调节作用。

• 原文标题及出处：
  

6-(Azaindol-2-yl)pyridine-3-sulfonamides as potent and selective inhibitors targeting hepatitis C virus NS4B

Bioorganic & Medicinal Chemistry Letters 25 (2015) 781–786

doi:10.1016/j.bmcl.2014.12.093

公司/组织：Merck

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靶点/作用机制：HCV抑制剂

摘要原文：

A structure–activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2 nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.

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• 原文标题及出处：
  

The discovery of novel 3-(pyrazin-2-yl)-1H-indazoles as potent pan-Pim kinase inhibitors

Bioorganic & Medicinal Chemistry Letters 25 (2015) 834–840

doi:10.1016/j.bmcl.2014.12.068

公司/组织：Amgen

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靶点/作用机制：PIM抑制剂

摘要原文：

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.

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• 原文标题及出处：
  

The discovery and optimization of aminooxadiazoles as potent Pim kinase inhibitors

Bioorganic & Medicinal Chemistry Letters 25 (2015) 847–855

doi:10.1016/j.bmcl.2014.12.067

公司/组织：Amgen

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靶点/作用机制：PIM抑制剂

摘要原文：

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers. These findings suggest that inhibition of Pim signaling by a small molecule Pim-1,2 inhibitor could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal starting from the highly Pim-selective indole–thiadiazole compound (1), which was derived from a nonselective hit identified in a high throughput screening campaign. Optimization of this compound’s potency and its pharmacokinetic properties resulted in the discovery of compound 29. Cyclopropane 29 was found to exhibit excellent enzymatic potency on the Pim-1 and Pim-2 isoforms (Ki values of 0.55 nM and 0.28 nM, respectively), and found to inhibit the phosphorylation of BAD in the Pim-overexpressing KMS-12 cell line (IC50 = 150 nM). This compound had moderate clearance and bioavailability in rat (CL = 2.42 L/kg/h; %F = 24) and exhibited a dose-dependent inhibition of p-BAD in KMS-12 tumor pharmacodynamic (PD) model with an EC50 value of 6.74 μM (18 μg/mL) when dosed at 10, 30, 100 and 200 mg/kg po in mice.

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• 原文标题及出处：
  

Discovery of indole-derived pyridopyrazine-1,6-dione γ-secretase modulators that target presenilin

Bioorganic & Medicinal Chemistry Letters 25 (2015) 908–913

doi:10.1016/j.bmcl.2014.12.059

公司/组织：Pfizer

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靶点/作用机制：γ-分泌酶调节剂

摘要原文：

Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aβ42 was achieved in a rat efficacy model when dosed orally at 30 mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.

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• 原文标题及出处：
  

Pyridine and pyridinone-based factor XIa inhibitors

Bioorganic & Medicinal Chemistry Letters 25 (2015) 925–930

doi:10.1016/j.bmcl.2014.12.050

公司/组织：Bristol-Myers Squibb

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靶点/作用机制：凝血因子Xia抑制剂

摘要原文：

The structure–activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs.

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• 原文标题及出处：
  

Synthesis and biological evaluation of adamantane-based aminophenols as a novel class of antiplasmodial agents

Bioorganic & Medicinal Chemistry Letters 25 (2015) 952–955

doi:10.1016/j.bmcl.2014.12.037

公司/组织：AstraZeneca

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靶点/作用机制：抗疟原虫药

摘要原文：

A series of adamantane based aminophenol derivatives were synthesized and evaluated for their antiplasmodial activity in vitro against Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1). Herein, we report compounds resulting from this work that show excellent potency against both strains. Additionally, this series displayed excellent cytotoxicity selectivity index against THP1 cell line and had acceptable in vitro DMPK properties.

备注：

• 原文标题及出处：
  

Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators

Bioorganic & Medicinal Chemistry Letters 25 (2015) 956–959

doi:10.1016/j.bmcl.2014.12.027

公司/组织：杨森

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靶点/作用机制：组胺H4受体调节剂

摘要原文：

Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (–NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.

备注：

(by 浮米网)

，抗疟疾药难道又有新品种了？！

谢谢楼主分享。

学习一下！

感谢楼主分享