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金虫 (小有名气)

应助: 2 (幼儿园)
金币: 1909.7
散金: 2
帖子: 179
在线: 93.6小时
虫号: 851856
注册: 2009-09-19
性别: GG
专业: 药物设计与药物信息

[交流] 浮米每周文献快讯：2014年3月（二）已有1人参与

1. Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib

期刊：J. Med. Chem., 2014, 57 (4), pp 1170–1187

DOI: 10.1021/jm401805h

公司/组织：Pfizer

相关候选药物化学结构及活性：201403100101

靶点/作用机制：间变性淋巴瘤激酶(ALK)

摘要原文：Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

备注：间变性淋巴瘤激酶(ALK)是胰岛素受体家族成员。第一个被FDA批准的ALK抑制剂是克唑替尼Crizotinib（商品名Xalkori，辉瑞），自2011年起作为治疗ALK阳性的肺癌一线用药。但是对克唑替尼产生耐药性成为影响治疗的一个重要问题。

2. Euodenine A: A Small-Molecule Agonist of Human TLR4

期刊：J. Med. Chem., 2014, 57 (4), pp 1252–1275

DOI: 10.1021/jm401321v

公司/组织：AstraZeneca

相关候选药物化学结构及活性：201403100102

靶点/作用机制：Toll样受体4（TLR4）激动剂

摘要原文：A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.

备注：TLRs是预防和治疗癌症、感染、过敏、哮喘、自身免疫疾病以及慢性神经性疼痛的重要靶点。TLR4激动剂有望成为治疗急性哮喘的药物。

3. Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

期刊：J. Med. Chem., 2014, 57 (4), pp 1276–1288

DOI: 10.1021/jm401326j

公司/组织：GlaxoSmithKline

相关候选药物化学结构及活性：201403100103

靶点/作用机制：InhA

摘要原文：Tuberculosis (TB) is one of the world’s oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure–activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.

备注：InhA是结核杆菌II型脂肪酸合成酶通路中NADH依赖性enoyl-酰基载体蛋白(ACP)还原酶。InhA是目前抗结核一线用药异烟肼的主要靶点。

4. Discovery of Isoquinolinone Indole Acetic Acids as Antagonists of Chemoattractant Receptor Homologous Molecule Expressed on Th2 Cells (CRTH2) for the Treatment of Allergic Inflammatory Diseases

期刊：J. Med. Chem., 2014, 57 (4), pp 1299–1322

DOI: 10.1021/jm401509e

公司/组织：Pfizer

相关候选药物化学结构及活性：201403100104

靶点/作用机制：Th2细胞表达的化学引诱物受体同源分子(CRTH2)拮抗剂

摘要原文：Previously we reported the discovery of CRA-898 (1), a diazine indole acetic acid containing CRTH2 antagonist. This compound had good in vitro and in vivo potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. However, it showed low oral exposure in nonrodent safety species (dogs and monkeys). In the current paper, we wish to report our efforts to understand and improve the poor PK in nonrodents and development of a new isoquinolinone subseries that led to identification of a new development candidate, CRA-680 (44). This compound was efficacious in both a house dust mouse model of allergic lung inflammation (40 mg/kg qd) as well as a guinea pig allergen challenge model of lung inflammation (20 mg/kg bid).

备注：CRTH2高表达以及对配体PGD2的高响应都可能是哮喘的原因。CRTH2拮抗剂用于治疗过敏性鼻炎、哮喘和COPD已进入临床试验阶段。

5. Design, Synthesis, and Evaluation of Conformationally Restricted Acetanilides as Potent and Selective β3 Adrenergic Receptor Agonists for the Treatment of Overactive Bladder

期刊：J. Med. Chem., 2014, 57 (4), pp 1437–1453

DOI: 10.1021/jm4017224

公司/组织：Merck

相关候选药物化学结构及活性：201403100105

靶点/作用机制：选择性β3肾上腺素受体(β3-AR)激动剂

摘要原文：A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.

备注：膀胱过度活动症是常见的排尿功能障碍的临床表现之一, 亦是目前国内外的研究热点。近年研究发现β3肾上腺素受体(β3—AR)是介导逼尿肌舒张的重要因素。

6. Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2–p53 Inhibitor in Clinical Development

期刊：J. Med. Chem., 2014, 57 (4), pp 1454–1472

DOI: 10.1021/jm401753e

公司/组织： Amgen Inc.

相关候选药物化学结构及活性：201403100106

靶点/作用机制：MDM2–p53

摘要原文：We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2–p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

备注：野生型p53存在于大部分肿瘤中，其功能受到MDM2（鼠双微体2）的调节。阻断MDM2-p53被认为是激活p53通路的有效途径。

7. Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects

期刊：J. Med. Chem., 2014, 57 (4), pp 1583–1598

DOI: 10.1021/jm4019178

公司/组织： Boehringer Ingelheim Pharmaceuticals, Inc.

相关候选药物化学结构及活性：201403100107

靶点/作用机制：糖皮质激素受体(GR)激动剂

摘要原文：Synthesis and structure–activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain “diazaindole” moieties and display different transcriptional regulatory profiles in vitro and are considered “dissociated” between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.

（by 浮米网）

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