CAS: 149709-44-4; (2R,4S)-5-([1,1'-Biphenyl]-4-yl)-4-(3-Carboxypropanamido)-2-Methylpentanoic Acid

上下游产品

沙库巴曲 Sacubitril 149709-62-6
Lcz700杂质 (2R,4S)-5-([1,1'-Biphenyl]-4-yl)-4-(2,5-Dioxopyrrol-1-yl)-2-Methyl Pentanoate 1038924-97-8

沙库巴曲置于recombinant Human Carboxylesterase 1体系中,用 Aq. Phosphate Buffer 用作溶剂,化学反应 2.0H,反应生成Lcz696杂质900-04
参考文献:Sacubitril Is Selectively Activated By Carboxylesterase 1 (Ces1) In The Liver And The Activation Is Affected By Ces1 Genetic Variation
标题:Sacubitril Is Selectively Activated By Carboxylesterase 1 (Ces1) In The Liver And The Activation Is Affected By Ces1 Genetic Variation
摘要:萨库比利(sacubitril)最近获得食品药品监督管理局(fda)的批准,可与缬沙坦(valsartan)联合使用,治疗射血分数降低的心力衰竭患者.作为前药,萨库比利必须被代谢(水解)为其活性代谢物萨库比利拉特(lbq657),才能发挥其预期的治疗效果.因此,了解萨库比利活化的决定因素将有助于改善萨库比利的药物治疗.这项研究的目标是识别负责萨库比利活化的酶,并确定遗传变异对萨库比利活化的影响.首先,进行了一项萨库比利与人类血浆及人类肝脏,肠道和肾脏的s9部分的孵育研究.研究发现,萨库比利仅在人体肝脏s9部分被激活.此外,萨库比利的活化受到羧酸酯酶1(ces1)抑制剂二-(对硝基苯基)磷酸酯在人体肝脏s9中的显著抑制.与重组人类ces1和羧酸酯酶2的进一步孵育研究确认了萨库比利是ces1的选择性底物.对转染了野生型ces1和ces1变异体g143E(rs71647871)的细胞系进行的体外研究表明,G143E是萨库比利活化的功能丧失变异体.重要的是,在携带g143E变异体的人类肝脏中,萨库比利的活化显著受损.总之,萨库比利在人体肝脏中是被ces1选择性激活的.Ces1遗传变异体g143E可以显著损害萨库比利的活化.因此,Ces1遗传变异体似乎是导致个体之间萨库比利活化差异的重要因素,并有潜力作为生物标志物来优化萨库比利的药物治疗.
Doi:10.1124/dmd.115.068536

专利信息

专利号:US-11161803-B2
优先权日:2017-04-28
标题:Ammonium carboxylate compound, crystalline form, amorphous form and preparation method thereof
发明人：ZHANG BO; DING XIAOHUA; DAI DONGCHENG; LEI SIJUN; LIU XUEMING; DUAN PANPAN; CHEN YONGKAI; WANG CHAODONG
权利人:WUHAN LL SCIENCE & TECHNOLOGY DEVELOPMENT CO LTD
摘要:The present disclosure belongs to the field of chemical synthesis, and in particular relates to an ammonium carboxylate compound, a crystalline form and an amorphous form, and a preparation method thereof. The present disclosure prepares the compound and the crystalline form I and its single crystal, amorphous form and crystalline form II thereof. The compound, the crystalline forms, the single crystal and the amorphous form can stably exist and exhibit good solid forms, suitable for medicine-making. Furthermore, these products possess high purity and less single impurity. Moreover, the preparation methods of the present disclosure are easy to implement due to the simple processes with mild reaction conditions, and could produce products of high yield and high purity without complex purification steps. Furthermore, the preparation methods may facilitate safety, environmental protection, and industrial production.