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汤森路透8月药物快讯

已有 4598 次阅读 2015-9-13 13:55 |个人分类:信息交流|系统分类:科研笔记

 

许老师,您好!

周末,此刻的我坐在电脑前,打开邮箱与您分享汤森路透8月药物快讯。每当这个时候是我最安静也最想表达些什么的时候。最近出差比较多,有些感触,仿佛对我从事的工作有了更深层次的理解。三年多的工作让我体会到数据库不是万能的,它的价值在于能够帮助我们在最短的时间内做到信息对称,能够为我们的决策提供更有力的客观数据支撑,我们每个人的每一天何尝不是在跟时间赛跑,时间就是金钱。

我们一直相信将正确的信息传递给正确的人,会产生非凡的力量。所以,我们会继续坚持传递与分享!

关于汤森路透更多药物资讯,您也可以扫描我们的官方微信二维码,也可以加我的个人微信(Jingzhi_1987_Sara),我会定期在朋友圈分享汤森路透的重磅文章,网络在线培训,线下活动等。

祝,周末愉快!

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汤森路透20158月药物快讯帮助您及时掌握药物研发最新动态

镇痛与麻醉 Analgesia & AnesthesiaAAK1抑制剂显示出治疗神经性疼痛的潜能

来自百时美施贵宝的研究者已经透露了BMS-911172,为一种脑渗透性AP2相关蛋白激酶1AAK1-选择抑制剂。使用一种小鼠基因敲除法联合疼痛状态评价,以寻求新的治疗靶点。发现AAK1有治疗神经性疼痛的潜能。针对持续疼痛实施的福尔马林分析中,AAK1敲除小鼠显示疼痛情况减轻,且神经性疼痛相关Chung模型中,显示神经性疼痛应答(机械性异常疼痛)降低,且不产生活动受损。BMS-911172的发明源于一系列以芳基酰胺为基础-AAK1抑制剂的SAR研究(酶类和细胞中分别为IC50 = 1251 nM)。针对Chung小鼠模型(60 mg/kg皮下给药)和慢性缩窄性损伤导致的热痛觉过敏和机械性异常疼痛的大鼠模型(60 mg/kg)实施了福尔马林分析,抑制剂在这些分析中显示有活性。小鼠中的PD标记物分析显示,在脑中对AAK1底物mu-2的磷酸化有抑制作用,呈剂量依赖性。所检验的剂量没有运动副作用。总之,这些研究结果为神经性疼痛提供了一种新的治疗方法(Hartz, R. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 334)。

AAK1 inhibitor shows potential for the treatment of neuropathic pain

Investigators from Bristol-Myers Squibb have disclosed BMS-911172, a brain-penetrant, AP2-associated protein kinase 1 (AAK1)-selective inhibitor. A mouse gene knockout approach combined with evaluation of pain behavior was used to look for novel therapeutic targets. AAK1 was identified as a potential target for neuropathic pain. AAK1 knockout mice displayed decreased pain behavior in the formalin assay for persistant pain and a reduced neuropathic pain response (mechanical allodynia) in the Chung model for neuropathic pain without producing motor impairment. SAR studies of a series of aryl amide-based AAK1 inhibitors led to the discovery of BMS-911172 (IC50 = 12 and 51 nM in enzymes and cells, respectively). The inhibitor was active in the formalin assay in the Chung mouse model (60 mg/kg s.c.) as well as in the chronic constriction injury-induced thermal hyperalgesia and mechanical allodynia rat model (60 mg/kg). PD marker assay in mice showed a dose-dependent inhibition of phosphorylation of AAK1 substrate mu-2 in the brain. There were no motor side effects at the doses tested. Taken together, these findings provide a novel method for the treatment of neuropathic pain (Hartz, R. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 334).

 

癌症 CancerExelixiscobimetinib首次在瑞士得到主管当局许可

Swissmedic批准将ExelixisCotellicTM)(cobimetinib)与vemurafenib联合使用,用于治疗晚期黑色素瘤患者。CobimetinibMEK的选择性抑制剂,由Exelixis公司发明,是Exelixis和基因泰克公司全球合作协议对象。Roche向瑞士主管当局提交的cobimetinib相关文件基于coBRIM所得数据,后者是一项针对cobimetinibvemurafenibIII期关键研究,在495例患者中实施此项研究,这些患者患有既往未经治疗的不可切除、局部晚期或转移性黑色素瘤,并有BRAF V600突变(ClinicalTrials.gov Identifier NCT01689519)。其他法规申请文件正就其他领域接受评审。2014年,基因泰克针对该药品向FDA提交了一份NDA,处方药用户费用法案日期为20151111日(见汤森路透药物新闻,201572日)。另外,罗氏在2014年晚些时候向EMA提交了一份MAA,并预期主管当局将在年底之前作出决定(Exelixis新闻稿)。

Exelixis receives first regulatory approval of cobimetinib in Switzerland

Swissmedic has approved Exelixis' Cotellic(TM) (cobimetinib) for use in combination with vemurafenib as a treatment for patients with advanced melanoma. Cobimetinib is a selective inhibitor of MEK that was discovered by Exelixis and is the subject of a worldwide collaboration agreement between Exelixis and Genentech. Roche's Swiss regulatory submission for cobimetinib was based on data from coBRIM, the phase III pivotal trial of cobimetinib and vemurafenib conducted in 495 patients with previously untreated unresectable, locally advanced or metastatic melanoma with a BRAF V600 mutation (ClinicalTrials.gov Identifier NCT01689519). Additional regulatory applications are under review in other territories. Genentech filed an NDA for the product with the FDA in 2014 and the Prescription Drug User Fee Act date is November 11, 2015 (see Thomson Reuters Drug News, July 2, 2015). Separately, Roche filed an MAA with the EMA in late 2014, and anticipates a regulatory decision before the end of the year (Exelixis News Release).

Merck KGaA和英国癌症研究院报告开发了Wnt信号通路抑制剂

来自Merck KGaA和伦敦癌症研究院的研究者们已经透露了一种有效的Wnt信号通路小分子抑制剂,有治疗结肠癌的潜能。Wnt信号通路在癌症干细胞的产生和维护方面发挥作用。通过以细胞为基础的高效筛选(HTS)鉴别出一系列吡啶类。进一步实施优选,以增加效用并改善理化性质和口服药代动力学。从所有化合物中选择了CCT-2519217dF3细胞系分析中为IC50 = 12 nM;细胞周期蛋白依赖性激酶8[CDK8]CDK19分别为IC50 = 89 nM)用于体内研究。对动物实施CCT-251921给药,剂量为0.2 mg/kg口服给药或0.5 mg/kg静脉给药。小鼠、大鼠和犬中,化合物的CL分别为102518 mL/min/kgVss分别为0.6321.4 L/kgF30%57%68%t1/2分别为0.780.930.99Mallinger, A. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 522)。

Merck KGaA and Cancer Research UK report development of Wnt signaling inhibitors

Investigators from Merck KGaA and the Institute of Cancer Research, London, have disclosed potent small-molecule inhibitors of Wnt signaling for the potential treatment of colon cancer. Wnt signaling has a role in the generation and maintenance of cancer stem cells. Cell-based high-throughput screening (HTS) led to the identification of a series of pyridines. Further optimization was performed to increase potency and improve physicochemical properties and oral pharmacokinetics. Among all compounds, CCT-251921 (IC50 = 12 nM in the 7dF3 cell line assay; IC50 = 8 and 9 nM for cyclin-dependent kinase 8 [CDK8] and CDK19, respectively), was selected for testing in vivo. Animals were administered CCT-251921 either at a dose of 0.2 mg/kg p.o. or 0.5 mg/kg i.v. The compound had CL of 10, 25, 18 mL/min/kg, Vss of 0.63, 2, 1.4 L/kg, F of 30, 57, 68% and t1/2 of 0.78, 0.93, 0.99 in mouse, rat and dog, respectively (Mallinger, A. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 522).

Amgen研究Pan-Pim激酶抑制剂的抗癌活性

Amgen发现了靶向丝氨酸/苏氨酸蛋白激酶pim-1-2-3Pim-1Pim-2Pim-3)的化合物,这些化合物与细胞存活和增殖相关,对其实施优化以测定它们在癌症中的潜在治疗活性。发现了一系列有效、有选择性和经口服生物可用的喹唑酮吡咯二氢吡咯酮类。这些化合物中最突出的是AM-6826,在小鼠异种移植模型中,剂量为50 mg/kg时,将KMS-12-BM黑色素肿瘤生长抑制了93%50 mg/kg一天两次给药与肿瘤衰退22%相关(Pettus, L. 250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 21)。

Pan-Pim kinase inhibitors investgated at Amgen for anticancer activity

Compounds targeting serine/threonine-protein kinase pim-1, -2 and -3 (Pim-1, Pim-2 and Pim-3), which are involved in cell survival and proliferation, have been discovered at Amgen and optimized to determine their potential therapeutic activity in cancer. A series of quinazolinone-pyrrolo-dihydropyrrolones was found to be potent, selective and orally bioavailable. Among these compounds was AM-6826, which inhibited growth of KMS-12-BM melanoma tumors in a mouse xenograft model by 93% when given at a dose of 50 mg/kg. A regimen of 50 mg/kg b.i.d. was associated with 22% tumor regression (Pettus, L. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 21).

皮肤病症 Dermatological DisordersVitae Pharmaceuticals公司提供了发现LXRβ激动剂的详情

来自Vitae Pharmaceuticals公司的研究者报告计划并发明了一种有效的口服活性肝脏X受体βLXRβ)激动剂,旨在用于治疗特应性皮炎和急性冠脉综合征。起点为Roche公司的一种化合物,对LXRβ有良好的选择性,超过LXRα。研究者使用专有的以结构为基础的药物设计平台Contour,后者通过计算机在靶点的活性结合位点构建药物样小分子,这些结合位点逐一结合可连接的药物样碎片。最初的例证显示对LXRβ有选择性,IC504 nM,超过LXRαIC50 = 43 nM)。进一步研究发明了VTP-766,选择性更佳(LXRβ IC50 = 3 nMLXRα IC50 = 81 nM)。化合物在细胞分析中也有活性(THP1细胞中,EC50 = 4.5 nM),且稳定性适中(CYP2C9大约为700 nM)。剂量范围为1-10mg/kg时,它在食蟹猴体内也有活性(Zheng, Y. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 16)。

Vitae Pharmaceuticals gives details on discovery of LXRbeta agonist

Investigators from Vitae Pharmaceuticals have reported the design and discovery of a potent orally active liver X receptor beta (LXRbeta) agonist targeted for the treatment of atopic dermatitis and acute coronary syndrome. The starting point was a compound from Roche with good selectivity for LXRbeta over LXRalpha. Researchers used the proprietary structure-based drug design platform Contour, which computationally builds drug-like small molecules in the target's active binding site combining drug-like fragments that can be connected, one by one. An initial lead demonstrated a selectivity for LXRbeta with an IC50 of 4 nM over LXRalpha (IC50 = 43 nM). Further studies led to the discovery of VTP-766 with an improved selectivity (LXRbeta IC50 = 3 nM, LXRalpha IC50 = 81 nM). The compound was also active in cellular assays (EC50 = 4.5 nM in THP1 cells) and had moderate stability (CYP2C9 approximately 700 nM). It was also active in vivo in cynomolgus monkeys at a dose range of 1 to 10 mg/kg (Zheng, Y. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 16).

内分泌紊乱病症 Endocrine DisordersFDA批准首次用于治疗女性性心理障碍

FDA已批准将Sprout Pharmaceuticals公司的AddyiTM)(氟班色林)实施每日一次给药,用于治疗绝经前女性获得性泛发型性心理障碍(HSDD)。公司预期在20151017日将Addyi推向市场。氟班色林是一种血清素5-HT1A受体激动剂和5-HT2A受体拮抗剂,可导致低血压或晕厥,与酒精或细胞色素P450 3A4CYP3A4)抑制剂联合使用时尤为如此。因此,FDA批准药物时带有风险评价和缓解策略(REMS),包括处方医生培训,并要求药剂师使用医患协议表,以告知女性在使用Addyi时勿饮酒。药物标签还包含一个带框的警告,忌用于饮酒者、使用CYP3A4抑制剂的患者和肝损伤患者。NDA基于三项双盲、安慰剂对照III期研究,在大约2400例绝经前女性中实施,这些女性患有获得性泛发型HSDD。与安慰剂相比,使用100 mg氟班色林治疗增加了满意性生活的数量,每月性生活增加0.5-1.0次,性欲评分增加0.3-0.4分,性欲相关苦恼评分降低0.3-0.4分。这些研究中,大约10%的氟班色林治疗参与者报告相对于这些终点取得有意义的改善(FDA新闻稿;Sprout Pharmaceuticals公司新闻稿)。

FDA approves first treatment for hypoactive sexual desire disorder in women

The FDA has approved Sprout Pharmaceuticals' Addyi(TM) (flibanserin) for the once-daily treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. The company expects to launch Addyi by October 17, 2015. Flibanserin is a serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist that can cause hypotension or syncope, especially if combined with alcohol or cytochrome P450 3A4 (CYP3A4) inhibitors. Therefore, the FDA has approved the drug with a Risk Evaluation and Mitigation Strategy (REMS) that includes training for prescribers and a requirement for pharmacists to use a Patient-Provider Agreement Form to advise women not to drink alcohol when using Addyi. The drug label also contains a boxed warning that it is contraindicated in alcohol drinkers, those taking CYP3A4 inhibitors and patients with liver impairment. The NDA was based on three double-blind, placebo-controlled phase III trials in approximately 2,400 premenopausal women with acquired, generalized HSDD. Versus placebo, treatment with 100 mg flibanserin increased the number of satisfying sexual events by 0.5-1.0 additional events per month, increased the sexual desire score by 0.3 to 0.4, and decreased the distress score related to sexual desire by 0.3 to 0.4. Approximately 10% of flibanserin-treated participants in these trials reported meaningful improvements against these endpoints (FDA News Release; Sprout Pharmaceuticals News Release).

肠胃道病症 Gastrointestinal Disorders显示ORAI1抑制剂有治疗胰腺炎的潜能

来自CalciMedica的科学家以及他们的合作者已经报告了钙释放-活化钙通道蛋白(ORAI1)抑制剂-GSK-7975ACM-128用于预防人类胰腺腺泡细胞的细胞内钙相关损伤和急性胰腺炎。于小鼠和人类腺泡细胞中实施的体外研究表明,CM-128抑制ICRAC),IC500.1 mcmol/L,为直接浓度依赖性。GSK-7975ACM-128抑制坏死细胞死亡通道激活。GSK-7975ACM-128分别抑制毒素诱导的ORAI1活化和/或在Ca2+释放后抑制Ca2+电流激活(抑制超过对照细胞中所观察到水平的90%),为浓度依赖性。在体内,于三种不同的急性胰腺炎临床代表性模型(TLCS-APCER-APFAEE-AP)中检验这两种化合物。所有三个模型中,急性胰腺炎的所有局部和全身特征均受到GSK-7975ACM-128的抑制,呈时间和剂量依赖性。在参数范围内,与诱发胰腺炎后6小时给药相比,诱发胰腺炎后一小时给药时抑制剂更有效。这些研究结果表明,ORAI1介导的细胞内钙超载归因于急性胰腺炎的发病机制。因此,ORAI1抑制剂可用于治疗胰腺炎。当前,CM-128正在接受临床前毒理学评价,随后将进入I期临床研究(Li, W. et al.Gastroenterology 2015, 1492:481)。

ORAI1 inhibitors show potential for the treatment of pancreatitis

Scientists from CalciMedica and their collaborators have reported results of calcium release-activated calcium channel protein 1 (ORAI1) inhibitors, GSK-7975A and CM-128, for the prevention of cytosolic calcium-associated injury of human pancreatic acinar cells and acute pancreatitis. In vitro analyses in mouse and human acinar cells showed that CM-128 inhibited I(CRAC) with an IC50 of 0.1 mcmol/L in a direct concentration-dependent matter. Both GSK-7975A and CM-128 inhibited necrotic cell death pathway activation. GSK-7975A and CM-128 each separately suppressed toxin-induced activation of ORAI1 and/or activation of Ca2+ currents after Ca2+ release (inhibition over 90% of the levels observed in control cells) in a concentration-dependent manner. In vivo, both compounds were tested in three diverse, clinically representative models of acute pancreatitis (TLCS-AP, CER-AP and FAEE-AP). All local and systemic features of acute pancreatitis were inhibited by GSK-7975A and CM-128 in all three models in a time- and dose-dependent manner. In a range of parameters, the inhibitors were more effective when administered 1 vs. 6 hours after induction of pancreatitis. These findings suggest that ORAI1-mediated cytosolic calcium overload contributes to the pathogenesis of acute pancreatitis. Therefore, ORAI1 inhibitors may be useful for the treatment of pancreatitis. Currently, CM-128 is undergoing preclinical toxicologic evaluation before entering phase I clinical studies (Li, W. et al. Gastroenterology 2015, 149(2): 481).

免疫调节药物 Immunomodulating Agents类克(英夫利西单抗)在日本获得批准用于治疗肠贝赫切特、神经贝赫切特、血管贝赫切特病

三菱田边制药获得日本的批准部分改动类克(R)(英利昔单抗)已经获得批准的信息,若现存治疗不充分,则静脉输注100与肠贝赫切特、神经贝赫切特、血管贝赫切特病的其他适应证相关。2007年,类克被批准用于治疗伴有难治性葡萄膜视网膜炎的贝赫切特病,然而这项新许可涵盖了较大范围的病情,并促成治疗几乎所有的III期或以上贝赫切特病患者。今年年初,公司还提交了一份类克的批准文件,用于治疗川崎病(见汤森路透药物新闻,2015518)(Mitsubishi Tanabe Pharma新闻稿)。

Remicade approved in Japan for entero-Behcet's, neuro-Behcet's and vasculo-Behcet's disease

Mitsubishi Tanabe Pharma has obtained Japanese approval for a partial change of approved information on Remicade(R) (infliximab) for intravenous infusion 100 in relation to additional indications for entero-Behcet's disease, neuro-Behcet's disease and vasculo-Behcet's disease in cases where existing treatment is inadequate. Remicade was approved in 2007 for Behcet's disease with refractory uveoretinitis, however this new approval covers a wider range of disease conditions and contributes to the treatment of nearly all patients with Behcet's disease of Stage III or higher. Earlier this year, the company also filed for approval of Remicade for the treatment of Kawasaki disease (see Thomson Reuters Drug News, May 18, 2015) (Mitsubishi Tanabe Pharma News Release).

感染 Infections第一三共宣告就补充适应证获得日本当局的批准

第一三共及其国内子公司第一三共 Espha已经宣称他们的药品获得了补充许可。第一三共的可乐必妥(R)(左氧氟沙星)片剂和颗粒剂,以及第一三共Espha的非专利版左氧氟沙星片250 mg DSEP500 mg DSEP和颗粒剂10% DSEP当前在日本获得批准,用于治疗肺病和肺结核的其他表征。左氧氟沙星是在日本获得批准用于治疗肺结核的唯一一种氟喹诺酮类药物。将其用作抗菌方案的一部分,用于治疗由于耐药或副作用而终止一线治疗的患者。第一三共的β1-肾上腺素受体拮抗剂ArtistR)(卡维地洛)已经在日本获得补充许可,口服用于治疗心动过速心房颤动。公司已实施了III期研究,表明使用卡维地洛心率降低(第一三共新闻稿)。

Daiichi Sankyo announces Japanese approvals for supplementary indications

Daiichi Sankyo and its domestic subsidiary Daiichi Sankyo Espha have announced supplementary approvals for their products. Daiichi Sankyo's Cravit(R) (levofloxacin) tablets and granules and Daiichi Sankyo Espha's generic versions Levofloxacin Tablets 250 mg DSEP and 500 mg DSEP and Granules 10% DSEP are now approved in Japan for the treatment of pulmonary and other manifestations of tuberculosis. Levofloxacin is the only fluoroquinoline approved for tuberculosis in Japan. It will be used as part of an antibacterial regimen in patients who discontinue first-line therapy because of drug resistance or side effects. Daiichi Sankyo's beta1-adrenoceptor antagonist Artist(R) (carvedilol) has received supplementary approval in Japan for the oral treatment of tachycardic atrial fibrillation. The company has conducted phase III trials and demonstrated a reduction in heart rate using carvedilol (Daiichi Sankyo News Releases).

Jacobus制药公司报告开发了新型抗疟药

来自Jacobus制药公司的研究者发明了2-氨基甲基苯酚抗疟药,在体外和体内有活性,能有效对抗疟原虫的血液阶段。实施了使用WR-194965 2-氨基甲基苯酚支架的SAR研究,旨在降低hERG活性并维持或增加抗疟能力。用三氟甲基取代的吡啶和嘧啶环代替氯苯基环,导致hERG抑制明显降低,并改善了抗疟活性。这一系列的两种早期类似物JPC-3186JPC-3210显示出抗P. falciparumW2系的体外研究活性(IC50分别为98 nM)。一项手动膜片钳分析中,10 mcM时,两种化合物对hERG电流的抑制不到20%。此外,JPC-3210在小鼠疟疾模型中显示出罕见的体内有效性,且有良好的药代动力学特征(16 mg/kg口服的tmax = 2小时,Cmax = 1180 ng/mLt1/2 = 169小时,AUC0-last=111000 h•ng/mLCl = 119 mL/h/kgF = 86%)。对小鼠实施剂量为4 mg/kg/天的JPC-3210口服给药治疗。所有接受治疗的P. berghei感染动物均存活(Hefferman, G. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 409)。

Jacobus Pharmaceutical reports development of novel antimalarials

Investigators from Jacobus Pharmaceutical have disclosed 2-aminomethylphenol antimalarials with potent in vitro and in vivo activity against Plasmodium blood stages. SAR studies using the 2-aminomethylphenol scaffold of WR-194965 were performed to decrease the hERG activity and maintain or increase antimalarial potency. The chlorophenyl ring was replaced with a trifluoromethyl-substituted pyridine or pyrimidine ring, which resulted in a significantly reduced hERG inhibition and improved antimalarial activity. Two advanced analogues from this series, JPC-3186 and JPC-3210, demonstrated potent in vitro activity against the W2 line of P. falciparum (IC50 of 9 and 8 nM, respectively). In a manual patch clamp assay, both compounds inhibited hERG current by less than 20% at 10 mcM. In addition, JPC-3210 demonstrated exceptional in vivo efficacy in a mouse malaria model and had a favorable pharmacokinetic profile (tmax = 2 hours, Cmax = 1,180 ng/mL, t1/2 = 169 hours, AUC(0-last) =111,000 h•ng/mL, Cl = 119 mL/h/kg and F = 86% for 16 mg/kg p.o.). Mice were treated with JPC-3210 at a dose of 4 mg/kg/day p.o. for 3 days. All treated animals infected with P. berghei survived (Hefferman, G. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 409).
These compounds have been described in the patent literature (WO 2014074775) .

代谢病症 Metabolic DisordersFDA批准将Keveyis用于治疗原发性高血钾和低血钾周期性麻痹

FDA已批注将Taro制药公司的KeveyisTM)(双氯非那胺)用于治疗原发性高血钾和低血钾周期性麻痹,为一组家族遗传病症,美国累及人数大约为5000人,导致肌无力和麻痹。公司预期在2015年第三季度将药品上市,并建立了患者支持程序(Taro制药公司新闻稿)。

FDA approves Keveyis for primary hyperkalemic and hypokalemic periodic paralysis

The FDA has approved Taro Pharmaceuticals' Keveyis(TM) (diclofenamide; dichlorphenamide) for the treatment of primary hyperkalemic and hypokalemic periodic paralysis, a group of genetic disorders, affecting approximately 5,000 people in the U.S., that cause muscle weakness and paralysis. The company expects to launch the drug in the third quarter of 2015 and has established a patient support program (Taro Pharmaceuticals News Release).

肌肉骨骼和结缔组织病症 Musculoskeletal & Connective Tissue Disorders全可利在日本获得批准,用于治疗全身硬皮病患者的新发手指溃疡

Actelion制药日本公司获得了另一项许可,关于内皮素受体拮抗剂全可利(R)片剂62.5 mg(波生坦水合物),用于减轻日本全身硬皮病患者的新发手指溃疡全可利当前就这一适应证在大约50个国家获得批准(Actelion新闻稿)。

Tracleer approved in Japan for new digital ulcers in patients with systemic scleroderma

Actelion Pharmaceutical Japan received an additional indication approval of the endothelin receptor antagonist Tracleer(R) Tablets 62.5 mg (bosentan hydrate) for the reduction of new digital ulcers in patients with systemic scleroderma in Japan. Tracleer is currently approved in around 50 countries for this indication (Actelion News Release).

神经病症 Neurologic DisordersFDA批准Aptiom作为癫痫部分发作的单一治疗

FDA已批准Sunovion制药公司的AptiomR)补充NDA(醋酸艾司利卡西平),作为癫痫部分发作的单一治疗。这一新适应证允许将Aptiom用作单一治疗,用于初治或从其他抗癫痫药物(AED)转换而来的患者。Aptiom既往在2013年获得批准,作为癫痫部分发作的辅助治疗。新的单一治疗许可基于两项关键III研究(研究093-045093-046)所得数据,达到FDA许可的预定主要终点(分别见ClinicalTrials.gov Identifiers NCT00866775NCT01091662)。相同设计的剂量设盲、历史对照、多中心、随机研究评价了醋酸艾司利卡西平(1600 mg/天或1200 mg/天)作为癫痫部分发作的单一治疗,在16岁或以上患者中的安全性和有效性,这些患者的癫痫发作经其他AED治疗未能得到良好控制。研究结果表明,转为接受醋酸艾司利卡西平单一治疗时,癫痫部分发作的患者中,退出率优于历史对照,这些患者通过接受一种或两种当前的AED未能得到良好控制。两种剂量规格的醋酸艾司利卡西平每日一次给药通常耐受性良好。最常见的治疗相关不良事件-头疼、头晕、疲劳、嗜睡、恶心的严重程度均为轻度或中度(Sunovion制药公司新闻稿)。

FDA approves Aptiom as monotherapy for partial-onset seizures

The FDA has approved the supplemental NDA for Sunovion Pharmaceuticals' Aptiom(R) (eslicarbazepine acetate) as monotherapy for the treatment of partial-onset seizures. This new indication allows Aptiom to be used as monotherapy in people who initiate treatment for the first time or convert from other antiepileptic drugs (AEDs). Aptiom was previously approved in 2013 as adjunctive therapy for partial-onset seizures. The new monotherapy approval was based on data from two pivotal phase III trials (Studies 093-045 and 093-046), which met the FDA-agreed prespecified primary endpoint (respectiveClinicalTrials.gov Identifiers NCT00866775 andNCT01091662). The identically designed, dose-blinded, historical-controlled, multicenter, randomized trials evaluated the safety and efficacy of eslicarbazepine acetate (1600 mg/day or 1200 mg/day) as monotherapy for partial-onset seizures in patients age 16 years or older whose seizures were not well controlled with other AEDs. Trial results showed that conversion to eslicarbazepine acetate monotherapy was associated with exit rates superior to historical controls in patients with partial-onset seizures, who were not well controlled by one or two current AEDs. Eslicarbazepine acetate administered once daily was generally well tolerated in both dose strengths. The most common treatment-related adverse events, headache, dizziness, fatigue, somnolence and nausea, were mainly mild or moderate in severity (Sunovion Pharmaceuticals News Release).

阿尔茨海默病中新的转运蛋白配体靶向线粒体功能障碍

干扰与淀粉样蛋白-β-诱导的线粒体功能障碍可受到与18Ka转运蛋白(TSPO)结合化合物的影响。根据TSPO配体的新支架,韩国科技大学、诚信女子大学和韩国科技研究院的研究者合成了噻吩并[2,3-d]嘧啶-4-单一化合物。HT22海马细胞中的评价(分析测量细胞活力、细胞脱氢酶的活性、线粒体膜电位、三磷酸腺苷的产生和活性氧)表明KST-013418为最有效的化合物。急性淀粉样蛋白诱导的阿尔茨海默病小鼠模型中,实施了一项Y-迷宫自发改变试验,腹膜内KST-013418给药改善了学习和记忆力。通过环境恐惧条件试验评估,疾病的APP/PS1转基因模型中,实施一个月的口服给药,恐惧相关学习记忆力也得到明显改善。正在进行KST-013418的优化(Kim, T.H. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 247)。

New translocator protein ligands target mitochondrial dysfunction in Alzheimer's disease

Interfering with amyloid-beta-induced mitochondrial dysfunction can be effected by compounds binding the 18Ka translocator protein (TSPO). From novel scaffolds of TSPO ligands, researchers from the Korean University of Science Technology, Sungshin Women's University and the Korea Institute of Science & Technology synthesized thieno[2,3-d]pyrimidin-4-one compounds. Evaluation in HT22 hippocampal cells (assays measuring cell viability, cellular dehydrogenase activity, mitochondrial membrane potential, adenosine triphosphate production and reactive oxygen species) indicated that KST-013418 was the most effective compound. Intraperitoneal KST-013418 improved learning and memory in a Y-maze spontaneous alteration test in an acute amyloid-beta-induced Alzheimer's disease mouse model. Oral administration for 1 month in the APP/PS1 transgenic model of the disease also significantly improved fear-associated learning memory as assessed in a contextual fear conditioning test. Optimization of KST-013418 is ongoing (Kim, T.H. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 247).

Merck & Co.针对AD发明了一系列新的BACE1抑制剂

波士顿正在举行的第250届美国化学学会(ACS)全国会议及博览会上,来自Merck & Co.的科学家报告发明了一种新型砜系列β-分泌酶1BACE1)抑制剂,用于治疗阿尔茨海默病(AD)。针对BACE抑制设计了一种新型不同结构的砜核,为了在MK-8931verubecestat)的噻嗪核周围进一步探查结构-活性关联(SAR),后者当前接受III期临床研究。对MK-8931的噻嗪实施一次原子修改(sp[2] N-sp[3] C)产生一个新的砜,具有极佳的生理化学特性。此核的各种类似物有强大的体外和细胞潜能,于临床前种群中大大减少了中心β淀粉样蛋白(),并具有良好的临床前安全性特征。对大鼠和猴子实施单次口服给药后,先导化合物MBI-19Ki = 3 nMIC50 = 2 nM;其选择性超过组织蛋白酶和其他天冬氨酸蛋白酶的1000倍,并有效减少了脑脊液Abeta40ED50大约为1 mg/kg。因此,每日一次低剂量化合物给药预期将使人类的Abeta40降低75%Wu, W.-L. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 13)。

Merck & Co. discloses novel series of BACE1 inhibitors for AD

At the ongoing 250th American Chemical Society (ACS) National Meeting & Exposition in Boston, scientists from Merck & Co. have reported the discovery of a novel sulfone series of beta-secretase 1 (BACE1) inhibitors for Alzheimer's disease (AD). A novel, structurally diversified sulfone core for BACE inhibition was designed to further explore structure-activity relationships (SAR) around the thiadiazine core of MK-8931 (verubecestat), which is currently in phase III clinical studies. The one atom modification (sp[2] N to sp[3] C) to the thiadiazine of MK-8931 resulted in a new sulfone with excellent physiochemical properties. Various analogues with this core had robust in vitro and cellular potency, excellent lowering of central beta-amyloid (Abeta) in preclinical species and a good preclinical safety profile. The lead compound, MBI-19, had Ki = 3 nM and IC50 = 2 nM; it showed greater than 1000-fold selectivity against cathepsin-D and other aspartyl proteases and a potent reduction of cerebral spinal fluid Abeta40 in rats and monkeys with an ED50 of 1 mg/kg, approximately, after single oral administration. Therefore, once-daily low dose of the compound was projected to achieve 75% reduction of Abeta40 in humans (Wu, W.-L. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 13).

呼吸病症 Respiratory Disorders显示MAP/MAPKAP-2抑制剂MK-2684有望治疗哮喘

来自Merck & Co.的研究者报告发明了一种有效的MAP/MAPKAP-2MK2)抑制剂,用于治疗哮喘。认为p38a MAP/MAPKAP-2可能是抑制促炎细胞因子的一种重要途径,且可避免CRP暂时抑制。开发了一类新型底物选择调节剂。化合物调节促炎细胞因子的生成。LPS攻击肺脏模型中,先导化合物(MK-2684)显示出有效性。在食蟹猴中进一步研究MK-2684,这些猴子接受30天治疗(通过雾化器给药,剂量为10 mg/mL,给药10分钟)。未发生不良事件。MK-2684显示出被选定为中度至重度哮喘吸入药物所需的安全性标准、物理和药代动力学特征(Dykstra, K. et al.250th Am Chem SocACSNatl MeetAug 16-20, Boston2015, Abst MEDI 331)。

MAP/MAPKAP-2 inhibitor MK-2684 shows promise for the treatment of asthma

Investigators from Merck & Co. have reported the discovery of a potent MAP/MAPKAP-2 (MK2) inhibitor for the treatment of asthma. It is thought that p38a MAP/MAPKAP-2 may be an essential pathway toward the inhibition of proinflammatory cytokines and could avoid transient inhibition of CRP. A novel class of substrate selective modulators was developed. The compounds regulated the production of proinflammatory cytokines. The lead compound (MK-2684) showed efficacy in an LPS challenge lung model. MK-2684 was further tested in rhesus monkeys that received treatment for 30 days (delivered by nebulizer at 10 mg/mL for 10 minutes). There were no adverse events. MK-2684 exhibited the requisite safety criteria, physical and pharmacokinetic properties to be selected as an inhaled agent for the treatment for moderate to severe asthma (Dykstra, K. et al. 250th Am Chem Soc (ACS) Natl Meet (Aug 16-20, Boston) 2015, Abst MEDI 331).

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Jingzhi Li(李敬芝)

IP & Science

Thomson Reuters

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