浮米每周文献快讯：2015年03月(一)

浮米每周文献快讯：2015年03月(一)前沿        作者：浮米网 来源：浮米网  2015-03-11

• 原文标题及出处：
  

Discovery of 1H-Pyrazol-3(2H)-ones as Potent and Selective Inhibitors of Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) J. Med. Chem., 2015, 58 (3), pp 1426–1441

DOI: 10.1021/jm5017494

公司/组织：Amgen

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靶点/作用机制：PERK抑制剂

摘要原文：

The structure-based design and optimization of a novel series of selective PERK inhibitors are described resulting in the identification of 44 as a potent, highly selective, and orally active tool compound suitable for PERK pathway biology exploration both in vitro and in vivo.

备注：

PERK、IRE1和ATF6是三个与未折叠蛋白反应（UPR）相关的感应器。调节UPR可作为癌症治疗手段。

• 原文标题及出处：
  

Synthesis and characterization of 1′-C-cyano-2′-fluoro-2′-C-methyl pyrimidine nucleosides as HCV polymerase inhibitors

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1046–1049

doi:10.1016/j.bmcl.2015.01.021

公司/组织：Gilead

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靶点/作用机制：HCV多聚酶抑制剂

摘要原文：

The first synthesis of 1′-C-CN, 2′-F, 2′-C-Me pyrimidines is described. Anti-HCV activity was assessed and compared to the 1′-C-CN, 2′-C-Me as well as the 2′-F, 2′-C-Me pyrimidines. A phosphoramidateprodrug of the cytidine derivative showed activity in the low micromolar range against HCV replicons.

备注：

• 原文标题及出处：
  

Synthesis and in vitro evaluation of novel 8-aminoquinoline–pyrazolopyrimidine hybrids as potent antimalarial agents

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1100–1103

doi:10.1016/j.bmcl.2015.01.003

公司/组织：AstraZeneca

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靶点/作用机制：抗疟药

摘要原文：

In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The medicinal chemistry approach to expand the scope of this series resulted in an identification of potent compounds with nanomolar potency (best IC50 5–10 nM). Systematic structure activity relationship (SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the critical interactions within pfDHODH drug target.

备注：

• 原文标题及出处：
  

Synthesis and SAR study of potent and selective PI3Kδ inhibitors

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1104–1109

doi:10.1016/j.bmcl.2015.01.001

公司/组织：Amgen

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靶点/作用机制：

                               
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PI3Kδ抑制剂

摘要原文：

2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties.

                               
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备注：

许多PI3Kδ选择性抑制剂，如idelalisib (GS-1101)、IPI-1455和AMG 3196已进入临床用于治疗血液系统恶性肿瘤。

                               
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• 原文标题及出处：
  

Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1135–1139

doi:10.1016/j.bmcl.2014.12.028

公司/组织：BoehringerIngelheim

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靶点/作用机制：HCV多聚酶抑制剂

摘要原文：

A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.

备注：

• 原文标题及出处：
  

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity

Bioorganic & Medicinal Chemistry Letters 25 (2015) 1140–1145

doi:10.1016/j.bmcl.2014.12.078

公司/组织：BoehringerIngelheim

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靶点/作用机制：HCV多聚酶抑制剂

摘要原文：

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8 × 11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients.

(by 浮米网)