 |
 |
 |
 |
 |
 |
||
 |
 |
 |
 |
 |
| 2 | 1/1 | 返回列表 |
| 查看: 952 | 回復(fù): 1 | ||||
xingchen7_金蟲 (小有名氣)
|
[交流]
浮米每周文獻(xiàn)快訊：2014年3月（二） 已有1人參與
|
|
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/組織：Pfizer 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100101 靶點(diǎn)/作用機(jī)制：間變性淋巴瘤激酶(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). 備注：間變性淋巴瘤激酶(ALK)是胰島素受體家族成員。第一個被FDA批準(zhǔn)的ALK抑制劑是克唑替尼Crizotinib（商品名Xalkori，輝瑞），自2011年起作為治療ALK陽性的肺癌一線用藥。但是對克唑替尼產(chǎn)生耐藥性成為影響治療的一個重要問題。 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/組織：AstraZeneca 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100102 靶點(diǎn)/作用機(jī)制：Toll樣受體4（TLR4）激動劑 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. 備注：TLRs是預(yù)防和治療癌癥、感染、過敏、哮喘、自身免疫疾病以及慢性神經(jīng)性疼痛的重要靶點(diǎn)。TLR4激動劑有望成為治療急性哮喘的藥物。 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/組織：GlaxoSmithKline 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100103 靶點(diǎn)/作用機(jī)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. 備注：InhA是結(jié)核桿菌II型脂肪酸合成酶通路中NADH依賴性enoyl-�；d體蛋白(ACP)還原酶。InhA是目前抗結(jié)核一線用藥異煙肼的主要靶點(diǎn)。 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/組織：Pfizer 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100104 靶點(diǎn)/作用機(jī)制：Th2細(xì)胞表達(dá)的化學(xué)引誘物受體同源分子(CRTH2)拮抗劑 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). 備注：CRTH2高表達(dá)以及對配體PGD2的高響應(yīng)都可能是哮喘的原因。CRTH2拮抗劑用于治療過敏性鼻炎、哮喘和COPD已進(jìn)入臨床試驗(yàn)階段。 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/組織：Merck 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100105 靶點(diǎn)/作用機(jī)制：選擇性β3腎上腺素受體(β3-AR)激動劑 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. 備注：膀胱過度活動癥是常見的排尿功能障礙的臨床表現(xiàn)之一, 亦是目前國內(nèi)外的研究熱點(diǎn)。近年研究發(fā)現(xiàn)β3腎上腺素受體(β3—AR)是介導(dǎo)逼尿肌舒張的重要因素。 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/組織： Amgen Inc. 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100106 靶點(diǎn)/作用機(jī)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). 備注：野生型p53存在于大部分腫瘤中，其功能受到MDM2（鼠雙微體2）的調(diào)節(jié)。阻斷MDM2-p53被認(rèn)為是激活p53通路的有效途徑。 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/組織： Boehringer Ingelheim Pharmaceuticals, Inc. 相關(guān)候選藥物化學(xué)結(jié)構(gòu)及活性：201403100107 靶點(diǎn)/作用機(jī)制：糖皮質(zhì)激素受體(GR)激動劑 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 浮米網(wǎng)） |
回復(fù)此樓» 收錄本帖的淘帖專輯推薦
 顓頊藥學(xué) |
» 猜你喜歡
酰胺脫乙�；�
已經(jīng)有13人回復(fù)
-
見刊快的中文核心期刊
已經(jīng)有2人回復(fù)
-
藥理學(xué)論文潤色/翻譯怎么收費(fèi)?
已經(jīng)有182人回復(fù)
-
一志愿天中醫(yī)中藥學(xué)專碩，希望有b區(qū)的老師可以考慮一下我
已經(jīng)有1人回復(fù)
-
調(diào)劑
已經(jīng)有2人回復(fù)
-
藥學(xué)學(xué)碩326求調(diào)劑
已經(jīng)有0人回復(fù)
-
26年博士申請
已經(jīng)有20人回復(fù)
-
求助 苯磷硫胺JP
已經(jīng)有0人回復(fù)
-
100金幣 阿莫西林克拉維酸鉀片BP藥典中提到的克拉維酸聚合物具體結(jié)構(gòu)式是啥？
已經(jīng)有2人回復(fù)
-
膳食補(bǔ)充劑合規(guī)性交流
已經(jīng)有0人回復(fù)
» 本主題相關(guān)商家推薦: (我也要在這里推廣)
» 本主題相關(guān)價值貼推薦，對您同樣有幫助:
- 中國物理快報-第三次換審稿人了(已發(fā)表)！
已經(jīng)有16人回復(fù)
pingzibuman
至尊木蟲 (著名寫手)
- 應(yīng)助: 49 (小學(xué)生)
- 金幣: 17359.1
- 散金: 22
- 紅花: 9
- 帖子: 2371
- 在線: 183.9小時
- 蟲號: 1103230
- 注冊: 2010-09-19
- 性別: GG
- 專業(yè): 合成藥物化學(xué)
2樓2014-03-11 09:25:00
相關(guān)版塊跳轉(zhuǎn)
我要訂閱樓主 xingchen7_ 的主題更新
| 2 | 1/1 | 返回列表 |
| 最具人氣熱帖推薦 [查看全部] | 作者 | 回/看 | 最后發(fā)表 | |
|---|---|---|---|---|
|
[考研] 一志愿北京化工大學(xué)0703化學(xué)318分，有科研經(jīng)歷，求調(diào)劑 +3 | 一瓶苯甲酸 2026-03-14 | 3/150 |
|
|---|---|---|---|---|
|
[考研] 304求調(diào)劑 +3 | 曼殊2266 2026-03-18 | 3/150 |
|
|
|
[考研] 286求調(diào)劑 +6 | lemonzzn 2026-03-16 | 10/500 |
|
|
|
[考研] 求調(diào)劑，一志愿:南京航空航天大學(xué)大學(xué) ，080500材料科學(xué)與工程學(xué)碩，總分289分 +3 | @taotao 2026-03-19 | 3/150 |
|
|
|
[考研] 一志愿 西北大學(xué) ，070300化學(xué)學(xué)碩，總分287，雙非一本，求調(diào)劑。 +3 | 晨昏線與星海 2026-03-19 | 3/150 |
|
|
|
[考研] 328求調(diào)劑，英語六級551，有科研經(jīng)歷 +4 | 生物工程調(diào)劑 2026-03-16 | 12/600 |
|
|
|
[考研] 一志愿985，本科211，0817化學(xué)工程與技術(shù)319求調(diào)劑 +10 | Liwangman 2026-03-15 | 10/500 |
|
|
|
[考研] 本科鄭州大學(xué)物理學(xué)院，一志愿華科070200學(xué)碩，346求調(diào)劑 +4 | 我不是一根蔥 2026-03-18 | 4/200 |
|
|
|
[考研] 295求調(diào)劑 +3 | 一志愿京區(qū)211 2026-03-18 | 5/250 |
|
|
|
[考研] 085600材料與化工 +5 | 安全上岸！ 2026-03-16 | 5/250 |
|
|
|
[考研] 311求調(diào)劑 +6 | 26研0 2026-03-15 | 6/300 |
|
|
|
[考研] 311求調(diào)劑 +11 | 冬十三 2026-03-15 | 12/600 |
|
|
|
[考研] 304求調(diào)劑 +12 | 小熊joy 2026-03-14 | 13/650 |
|
|
|
[考研] 0703化學(xué)調(diào)劑 +3 | 妮妮ninicgb 2026-03-17 | 3/150 |
|
|
|
[考研] 工科材料085601 279求調(diào)劑 +6 | 困于星晨 2026-03-17 | 6/300 |
|
|
|
[考研] 308求調(diào)劑 +4 | 是Lupa啊 2026-03-16 | 4/200 |
|
|
|
[考研] 材料專碩326求調(diào)劑 +6 | 墨煜姒莘 2026-03-15 | 7/350 |
|
|
|
[考研] 一志愿，福州大學(xué)材料專碩339分求調(diào)劑 +3 | 木子momo青爭 2026-03-15 | 3/150 |
|
|
|
[考研] 328求調(diào)劑 +3 | 5201314Lsy！ 2026-03-13 | 6/300 |
|
|
|
[碩博家園] 085600 260分求調(diào)劑 +3 | 天空還下雨么 2026-03-13 | 5/250 |
|