BACKGROUND & AIMS: PURPOSE:To determine the effect of latanoprost on the expression of human matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the trabecular meshwork (TM). METHODS:Total RNA was isolated, and qualitative RT-PCR was performed to detect the mRNA of MMPs and TIMPs in human TM tissue and explant cultures of TM endothelial cells. Cultures of TM cells were treated with vehicle control or latanoprost acid for 24 hours. Real-time RT-PCR of cell cultures from five different donors was performed to determine relative changes in expression. GAPDH served as an endogenous control. RESULTS:The mRNA of MMP-1, -2, -3, -11, -12, -14, -15, -16, -17, -19, and -24 and of TIMP-1 to -4 was present in TM tissue and cultures of TM cells. MMP-9 was not found. In control TM endothelial cells, the relative expression of MMP mRNA were MMP-2 and -14 > MMP-16, -19, and -24 > MMP-15 > MMP-11 and -17 > MMP-1 and -3 > MMP-12. The relative expressions of TIMP mRNA were TIMP-1 > TIMP-2 and -3 > TIMP-4. Latanoprost increased MMP-1 (in four of five cultures), MMP-3 (in four of five cultures), MMP-17 (in three of five cultures), MMP-24 (in all five cultures), TIMP-2, -3, and -4 expression (in three of five cultures); MMP-11 and -15 were downregulated. CONCLUSIONS:Contrary to the expected result, latanoprost seems to have a significant effect on TM cells. The transcription of the genes for MMP-1, -3, -17, and -24 is increased by latanoprost treatment. TIMP-2, -3, and -4 are also upregulated. The upregulation of these TIMPs may compensate for the increase of those MMPs. The absence of MMP-9 and concurrent upregulation of a greater number of TIMPs may explain the limited effect of latanoprost on TM outflow.

背景与目标：

BACKGROUND & AIMS: :Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.

背景与目标： : 基质金属蛋白酶 (MMPs) 由于其在肿瘤转移以及退行性疾病 (如骨关节炎和类风湿性关节炎) 的兴起和传播中的作用而成为深入研究的主题。初步设计了140类药物小分子基质metalloproteinase-3抑制剂，作为优化和合成的起始支架，使用一系列高度预测性的三维定量构效关系模型，包括比较分子场分析和比较分子相似性指数分析，对接和得分。沙利度胺被选为新铅系列的骨架，因为它适度抑制MMP-3，具有抗血管生成作用，并且易于进行结构修饰。根据辛醇-水分配系数ClogP估计，大多数新化合物表现出中等至高的预测生物活性和良好的生物利用度。化合物102尤其表现出对MMP-3极其有利的预测活性; 具有适度的生物利用度; 满足Lipinski的五法则; 并显示出有望进一步优化，合成和实验评估作为潜在的辅助抗癌或抗风湿治疗剂。

BACKGROUND & AIMS: BACKGROUND:Angiotensin-converting enzyme (ACE) inhibitors prevent the expansion and rupture of aortic aneurysms in animals. We investigated the association between ACE inhibitors and rupture in patients with abdominal aortic aneurysms. METHODS:We did a population-based case-control study of linked administrative databases in Ontario, Canada. The sample included consecutive patients older than 65 (n=15,326) admitted to hospital with a primary diagnosis of ruptured or intact abdominal aortic aneurysm between April 1, 1992, and April 1, 2002. FINDINGS:Patients who received ACE inhibitors before admission were significantly less likely to present with ruptured aneurysm (odds ratio [OR] 0.82, 95% CI 0.74-0.90) than those who did not receive ACE inhibitors. Adjustment for demographic characteristics, risk factors for rupture, comorbidities, contraindications to ACE inhibitors, measures of health-care use, and aneurysm screening yielded similar results (0.83, 0.73-0.95). Consistent findings were noted in subgroups at high risk of rupture, including patients older than 75 years and those with a history of hypertension. Conversely, such protective associations were not observed for beta blockers (1.02, 0.89-1.17), calcium channel blockers (1.01, 0.89-1.14), alpha blockers (1.15, 0.86-1.54), angiotensin receptor blockers (1.24, 0.71-2.18), or thiazide diuretics (0.91, 0.78-1.07). INTERPRETATION:ACE inhibitors are associated with a reduced risk of ruptured abdominal aortic aneurysm, unlike other antihypertensive agents. Randomised trials of ACE inhibitors for prevention of aortic rupture might be warranted.

背景与目标：

BACKGROUND & AIMS: :Type 2 diabetes is a complex metabolic disease with hyperglycemia as its recognizable hallmark. Hepatic glucose output is elevated in Type 2 diabetic patients, and evidence suggests drugs which lower hepatic glucose production are effective antihyperglycemic agents. Glycogenolysis, which is the release of monomeric glucose from its polymeric storage form called glycogen, is a key contributor to hepatic glucose output. Glycogen phosphorylase is the enzyme that catalyzes this process. This review covers advances in the design of small molecule inhibitors of this enzyme, their biological activity, and their potential as effective antihyperglycemic agents for the treatment of Type 2 diabetes.

背景与目标： 2型糖尿病是一种复杂的代谢性疾病，以高血糖为标志。2型糖尿病患者的肝葡萄糖输出升高，有证据表明降低肝葡萄糖产生的药物是有效的降血糖药。糖原分解，即单体葡萄糖从其称为糖原的聚合储存形式中释放出来，是肝葡萄糖输出的关键因素。糖原磷酸化酶是催化这一过程的酶。这篇综述涵盖了这种酶的小分子抑制剂的设计，其生物学活性及其作为治疗2型糖尿病的有效降糖药物的潜力的进展。

BACKGROUND & AIMS: :Cytochrome P450 enzymes are responsible for phase I metabolism of the majority of drugs and xenobiotics. Identification of the substrates and inhibitors of these enzymes is important for the analysis of drug metabolism, prediction of drug-drug interactions and drug toxicity, and the design of drugs that modulate cytochrome P450 mediated metabolism. The substrates and inhibitors of these enzymes are structurally diverse. It is thus desirable to explore methods capable of predicting compounds of diverse structures without over-fitting. Support vector machine is an attractive method with these qualities, which has been employed for predicting the substrates and inhibitors of several cytochrome P450 isoenzymes as well as compounds of various other pharmacodynamic, pharmacokinetic, and toxicological properties. This article introduces the methodology, evaluates the performance, and discusses the underlying difficulties and future prospects of the application of support vector machines to in silico prediction of cytochrome P450 substrates and inhibitors.

背景与目标： : 细胞色素P450酶负责大多数药物和异源生物的I期代谢。鉴定这些酶的底物和抑制剂对于分析药物代谢，预测药物-药物相互作用和药物毒性以及设计调节细胞色素P450介导的代谢的药物非常重要。这些酶的底物和抑制剂在结构上是多种多样的。因此，需要探索能够预测具有不同结构的化合物而不会过度拟合的方法。支持向量机是一种具有这些品质的有吸引力的方法，已用于预测几种细胞色素P450同工酶以及其他各种药效学，药代动力学和毒理学特性的化合物的底物和抑制剂。本文介绍了该方法，评估了性能，并讨论了支持向量机在细胞色素P450底物和抑制剂的计算机预测中的潜在困难和未来前景。

BACKGROUND & AIMS: MyristoylCoA:protein N-myristoyltransferase (NMT) catalyzes the cotranslational covalent attachment of a rare cellular fatty acid, myristate, to the N-terminal Gly residue of a variety of eukaryotic proteins. The myristoyl moiety is often essential for expression of the biological functions for these proteins.

Attachment of C14:0 alone provides barely enough hydrophobicity to allow stable association with membranes. The partitioning of N-myrisotylproteins is therefore often modulated by "switches" that function through additional covalent or noncovalent modifications. Candida albicans, the principal cause of systemic fungal infection in immunocompromised humans, contains a single NMT gene that is essential for its viability. The functional properties of the acylCoA binding site of human and C. albicans NMT are very similar. However, there are distinct differences in their peptide binding sites. An ADP ribosylation factor (Arf) is included among the few cellular protein substrates of the fungal enzyme. Alanine scanning mutagenesis of an octapeptide derived from an N-terminal Arf sequence (GLYASKLS-NH2) disclosed that Gly1, Ser5, and Lys6 play predominant roles in binding. ALYASKLS-NH2 is an inhibitor competitive for peptide [Ki(app) = 15.3 +/- 6.4 microM] and noncompetitive for myristoylCoA. Remarkably, replacement of the N-terminal tetrapeptide with an 11-aminoundecanoyl group results in a competitive inhibitor (11-aminoundecanoyl-SKLS-NH2) that is approximately 40-fold more potent [Ki(app) = 0.40 +/- 0.03 microM] than the starting octapeptide. Removal of Leu-Ser from the C-terminus generates a competitive dipeptide inhibitor (11-aminoundecanoyl-SK-NH2) with a Ki(app) of 11.7 +/- 0.4 microM, equivalent to that of the starting octapeptide. A derivative dipeptide inhibitor containing a C-terminal N-cyclohexylethyl lysinamide moiety has the advantage of being more potent (IC50 = 0.11 +/- 0.03 microM) and resistant to digestion by cellular carboxypeptidases. Rigidifying the flexible aminoundecanoyl chain results in very potent general NMT inhibitors (IC50 = 40-50 nM). Substituting a 2-methylimidazole for the N-terminal amine and adding a benzylic alpha-methyl group with R stereochemistry to the rigidifying element produces even more potent inhibitors (IC50 = 20-50 nM) that are up to 500-fold selective for the fungal compared to human enzyme. A related less potent member of this series of compounds is fungistatic. Its growth inhibitory effects are associated with a reduction in cellular protein N-myristoylation, judged using cellular Arf as a reporter. These studies establish that NMT is a new antifungal target.

背景与目标： 肉豆蔻酰辅酶a : 蛋白质N-肉豆蔻酰转移酶 (NMT) 催化稀有细胞脂肪酸肉豆蔻酸酯与多种真核蛋白质的N末端Gly残基的共翻译共价连接。肉豆蔻酰部分对于表达这些蛋白质的生物学功能通常是必不可少的。
C14的附着 :0仅提供了足够的疏水性，无法与膜稳定结合。因此，N-肉豆蔻基蛋白的分配通常由 “开关” 调节，该开关通过其他共价或非共价修饰起作用。白色念珠菌是免疫功能低下的人体全身性真菌感染的主要原因，它包含一个对其生存能力至关重要的NMT基因。人与白色念珠菌NMT的酰基辅酶a结合位点的功能特性非常相似。然而，它们的肽结合位点存在明显差异。真菌酶的少数细胞蛋白底物中包括ADP核糖基化因子 (Arf)。衍生自N-末端Arf序列 (GLYASKLS-NH2) 的八肽的丙氨酸扫描诱变揭示Gly1、Ser5和Lys6在结合中起主要作用。ALYASKLS-NH2是一种对肽 [Ki(app) = 15.3 +/- 6.4 microM] 有竞争力的抑制剂，对肉豆蔻酰辅酶a无竞争力。值得注意的是，用11-氨基十一酰取代N-末端四肽导致竞争性抑制剂 (11-氨基十一酰-skls-nh2) 的效力比起始八肽高约40倍 [Ki(app) = 0.40 +/- 0.03微米]。从C末端去除Leu-Ser会产生竞争性二肽抑制剂 (11-氨基十一酰-sk-nh2)，Ki(app) 为11.7 +/- 0.4微米，相当于起始八肽。含有C-末端N-环己基乙基赖氨酰胺部分的衍生物二肽抑制剂具有更有效 (IC50 = 0.11 +/- 0.03微米) 和对细胞羧肽酶消化的抗性的优点。硬化柔性氨基十一酰链会产生非常有效的通用NMT抑制剂 (IC50 = 40-50nm)。用2-甲基咪唑代替N-末端胺并将具有R立体化学的苄基 α-甲基添加到硬化元件中，产生甚至更有效的抑制剂 (IC50 = 20-50nm)，其对真菌的选择性与人酶相比高达500倍。该系列化合物中一个相关的效力较低的成员是真菌抑制剂。使用细胞Arf作为报告基因，其生长抑制作用与细胞蛋白N-肉豆蔻酰化的减少有关。这些研究表明，NMT是一种新的抗真菌靶标。

BACKGROUND & AIMS: :The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors that have potential value in the treatment of HIV/AIDS. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties. A series of novel ADAMs were therefore designed and synthesized in order to replace the metabolically labile methyl ester moieties of the existing ADAM lead compounds with hydrolytically stable, fused isoxazolone, isoxazole, oxazolone, or cyano substituents on the aromatic rings. The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity.

背景与目标： : 烯基二芳基甲烷 (ADAMs) 是一类独特的非核苷类逆转录酶抑制剂，在治疗HIV/AIDS中具有潜在价值。然而，ADAMs的潜在用途受到代谢不稳定的甲酯部分的存在的限制。因此，设计并合成了一系列新型的ADAMs，以便用水解稳定的，稠合的异恶唑酮，异恶唑，恶唑酮或芳环上的氰基取代基代替现有ADAM铅化合物的代谢不稳定的甲酯部分。母体化合物1中两个芳环上的甲酯和甲氧基取代基已成功地被代谢稳定的部分取代，并保留了抗HIV活性，细胞毒性普遍降低。

BACKGROUND & AIMS: :We studied the influence of aprotinin and soya bean trypsin inhibitor (SBTI) on the inflammatory reaction induced by the implantation of dry sponges in normal Wistar rats and in kininogen-deficient Brown Norway rats, during the first day after the implantation. In normal rats, aprotinin reduced the volume and total protein content of the exudates at 3 h but not thereafter. Aprotinin also markedly reduced the immunoreactive kinins and kallikrein in the exudates. Aprotinin did not modify the volume of the exudates of the Brown Norway rats. SBTI reduced the inflammatory reaction in both rat strains but did not significantly modify the formation of immunoreactive kinins. The inflammatory reaction developed more slowly in Brown Norway rats. The kinin system is thus involved during the first hours of the development of this acute inflammatory reaction. The anti-inflammatory effect of SBTI does not depend on the inhibition of kinin formation.

背景与目标： : 我们在植入后的第一天研究了抑肽酶和大豆胰蛋白酶抑制剂 (SBTI) 对正常Wistar大鼠和缺乏激肽原的棕色挪威大鼠中干海绵植入诱导的炎症反应的影响。在正常大鼠中，抑肽酶在3小时内减少了渗出物的体积和总蛋白含量，但此后并未减少。抑肽酶还显着降低了分泌物中的免疫反应性激肽和激肽释放酶。抑肽酶不会改变棕色挪威大鼠的渗出物的体积。SBTI降低了两种大鼠品系的炎症反应，但并未显着改变免疫反应性激肽的形成。棕色挪威大鼠的炎症反应发展较慢。因此，在这种急性炎症反应发生的最初几个小时内，激肽系统就参与其中。SBTI的抗炎作用不取决于激肽形成的抑制作用。

BACKGROUND & AIMS: :The fumigant insecticide phosphine (PH3) is known to inhibit cytochrome c oxidase in vitro. Inhibition of the respiratory chain at this site has been shown to stimulate the generation of superoxide radicals (O2-), which dismutate to form hydrogen peroxide (H2O2). This study was performed in order to investigate the production of H2O2 by mitochondria isolated from granary weevil (Sitophilus granarius) and mouse liver on exposure to PH3. Other respiratory inhibitors, antimycin, myxothiazol, and rotenone were used with insect mitochondria. Hydrogen peroxide was measured spectrophotometrically using yeast cytochrome c peroxidase as an indicator. Insect and mouse liver mitochondria, utilizing endogenous substrate, both produced H2O2 after inhibition by PH3. Insect organelles released threefold more H2O2 than did mouse organelles, when exposed to PH3. Production of H2O2 by PH3-treated insect mitochondria was increased significantly on addition of the substrate alpha-glycerophosphate. Succinate did not enhance H2O2 production, however, indicating that the H2O2 did not result from the autoxidation of ubiquinone. NAD(+)-linked substrates, malate and pyruvate also had no effect on H2O2 production, suggesting that NADH-dehydrogenase was not the source of H2O2. Data obtained using antimycin and myxothiazol, both of which stimulated the release of H2O2 from insect mitochondria, lead to the conclusion that glycerophosphate dehydrogenase is a source of H2O2. The effect of combining PH3, antimycin, and myxothiazol on cytochrome spectra in insect mitochondria was also recorded. It was observed that PH3 reduces cytochrome c oxidase but none of the other cytochromes in the electron transport chain. There was no movement of electrons to cytochrome b when insect mitochondria are inhibited with PH3. The spectral data show that the inhibitors interact with the respiratory chain in a way that would allow the production of H2O2 from the sites proposed previously.

背景与目标： : 熏蒸剂杀虫剂磷化氢 (PH3) 已知在体外抑制细胞色素c氧化酶。已显示在此位点对呼吸链的抑制可刺激超氧化物自由基 (O2-) 的产生，其歧化形成过氧化氢 (H2O2)。进行这项研究是为了研究暴露于ph3时从粮仓象鼻虫 (Sitophilus granarius) 和小鼠肝脏中分离出的线粒体产生H2O2。其他呼吸抑制剂，抗霉素，粘噻唑和鱼藤酮与昆虫线粒体一起使用。以酵母细胞色素c过氧化物酶为指示剂，分光光度法测定过氧化氢。昆虫和小鼠肝线粒体利用内源性底物，在被ph3抑制后均产生H2O2。当暴露于ph3时，昆虫细胞器释放的H2O2比小鼠细胞器多三倍。添加底物 α-甘油磷酸后，PH3-treated昆虫线粒体产生的H2O2显着增加。琥珀酸盐并不能提高H2O2的产生，这表明H2O2不是由泛醌的自氧化产生的。NAD () 连接的底物，苹果酸和丙酮酸对H2O2的产生也没有影响，这表明NADH-脱氢酶不是H2O2的来源。使用抗霉素和粘噻唑获得的数据均刺激了昆虫线粒体中H2O2的释放，得出的结论是甘油磷酸脱氢酶是H2O2的来源。还记录了PH3，抗霉素和粘噻唑对昆虫线粒体细胞色素光谱的影响。观察到PH3减少了细胞色素c氧化酶，但没有减少电子传递链中的其他细胞色素。当ph3抑制昆虫线粒体时，电子没有向细胞色素b移动。光谱数据表明，抑制剂与呼吸链相互作用的方式将允许从先前提出的位点产生H2O2。

BACKGROUND & AIMS: :Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer's or Parkinson's diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC(50)=350 nM; CDK5/p25, IC(50)=200 nM). These new molecules were synthesized using an original Buchwald-Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC(50) values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC(50) values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC(50) values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer's disease (3g, 3h, 4m; IC(50) values ranging from 300 to 400 nM).

背景与目标： : 细胞周期蛋白依赖性激酶5 (CDK5) 是属于细胞周期蛋白依赖性激酶 (CDK) 家族的丝氨酸/苏氨酸激酶。CDK5参与多种神经元疾病 (包括阿尔茨海默病或帕金森氏病，中风，创伤性脑损伤)，疼痛信号传导和细胞迁移。在本信中，我们描述了新的2,6，9-三取代嘌呤的合成和生物学评估，这些嘌呤在结构上与roscovitine有关，roscovitine是目前在临床试验中有希望的CDK抑制剂 (CDK1/Cyclin B，IC(50)= 350 nM; CDK5/p25，IC(50)= 200 nM)。这些新分子是使用原始的Buchwald-Hartwig催化程序合成的; 几种化合物 (3j，3k，3l，3e，4k，6b，6c) 显示出针对CDK5的有效激酶抑制能力 (IC(50) 值范围为17至50 nm)，并显示出显着的细胞死亡诱导活性 (IC(50) 值范围为2至9μm的SH-SY5Y)。抑制剂与CDK5催化位点的ATP结合结构域的对接突出了涉及CDK5 Lys-89的氢键的区分作用。此外，针对几种抑制剂测量的用于络合的计算的最终能量平衡与IC(50) 值的排名一致。最后，我们观察到几种化合物表现出对DYRK1A (双重特异性，酪氨酸磷酸化调节激酶1A) 的亚微摩尔活性，DYRK1A是一种与唐氏综合症和阿尔茨海默氏病有关的激酶 (3g，3h，4m; IC(50) 值范围从300到400 nM)。

BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.

背景与目标： : 设计，合成和评估了一系列新型白藜芦醇衍生物，可作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中，化合物7l，(E)-5-(4-(异丙基氨基) 苯乙烯基) 苯-1,3-二醇表现出有效的 β-淀粉样蛋白聚集抑制活性，通过ThT荧光分析 (71.65% 在20μm) 和透射电子显微镜 (TEM) 证实了这一点。化合物7l也显示出良好的抗氧化活性 (在氧自由基吸收能力分析中4.12的Trolox当量和10μm细胞中活性氧的37% 减少)。化合物的细胞毒性分析7f，7i，7j和7l表明这些化合物在60μm时的毒性比白藜芦醇低。

BACKGROUND & AIMS: :A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

背景与目标： : 已经确定了一系列新型的有效且有效的Xa因子抑制剂，该抑制剂在邻氨基苯甲酰胺化学型中具有磺胺嘧啶部分作为新型的S4结合元件。在这种新型P4组中进行铅优化可导致许多有效的Xa因子抑制剂在人血浆中具有出色的抗凝活性。将选定的化合物口服给大鼠，并检查其离体凝血酶原时间延长活性，结果鉴定了化合物5-氯-N-(5-氯吡啶-2-基)-2-(4-(N-(2-二乙基氨基) 乙酰基)-S-甲基磺酰亚胺基) 苯甲酰胺 (18f)。18f的详细药代动力学评估和随后的代谢研究表明存在活性代谢物。该化合物18f及其活性代谢物18b在大鼠动脉和静脉血栓形成模型中均表现出出色的体内功效，并被发现对相关丝氨酸蛋白酶具有高度选择性。基于这一前景，选择化合物18f进行进一步评估。

BACKGROUND & AIMS: :As a continuation of our efforts directed towards the development of anti-diabetic agents from natural sources, piplartine was isolated from Piper chaba, and was found to inhibit recombinant human ALR2 with an IC(50) of 160 μM. To improve the efficacy, a series of analogues have been synthesized by modification of the styryl/aromatic and heterocyclic ring functionalities of this natural product lead. All the derivatives were tested for their ALR2 inhibitory activity, and results indicated that adducts 3c, 3e and 2j prepared by the Michael addition of piplartine with indole derivatives displayed potent ARI activity, while the other compounds displayed varying degrees of inhibition. The active compounds were also capable of preventing sorbitol accumulation in human red blood cells.

背景与目标： : 作为我们致力于从天然来源开发抗糖尿病剂的努力的继续，从Piper chaba中分离出了piplatine，并发现其IC(50) 为160 μ m抑制重组人ALR2。为了提高功效，已通过修饰该天然产物铅的苯乙烯基/芳族和杂环官能团合成了一系列类似物。测试了所有衍生物的ALR2抑制活性，结果表明，通过将哌哌丁胺与吲哚衍生物的Michael加成制备的加合物3c，3e和2j表现出有效的ARI活性，而其他化合物则表现出不同程度的抑制作用。活性化合物还能够防止山梨醇在人红细胞中的积累。

BACKGROUND & AIMS: :Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second-generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising.

背景与目标： : 表皮生长因子受体 (EGFR) 的致敏突变可预测对EGFR酪氨酸激酶抑制剂 (TKIs) 的反应，并且第一代和第二代TKIs均可作为晚期EGFR突变型非小细胞肺癌患者的一线治疗选择。在重复活检和血浆循环肿瘤DNA中，最终的耐药性可通过多种机制识别。T790M网守突变负责几乎60% 的病例。许多第三代TKIs正在临床开发中，奥希替尼已获得美国食品药品监督管理局的批准，可用于治疗EGFR T790M突变型肺癌患者的初始EGFR激酶治疗失败。这些新药物的耐药机制正在被确定，并且EGFR突变型肺癌的治疗前景继续发展。EGFR TKIs的序列可能会在未来发生变化，针对耐药性的联合疗法似乎很有希望。

BACKGROUND & AIMS: :Two new families of human farnesyltransferase inhibitors 13a-m and 14a-d, based on a phenothiazine scaffold, were synthesized. Compounds 14a and 14b were the most promising inhibitors of human farnesyltransferase with IC(50) values of 0.7 and 0.6 μM, respectively.

背景与目标： : 合成了基于吩噻嗪支架的两个新的人法尼基转移酶抑制剂13a-m和14a-d家族。化合物14a和14b是最有希望的人法尼基转移酶抑制剂，其IC(50) 值分别为0.7和0.6。