149709-62-6
149709-62-6 結(jié)構(gòu)式
基本信息
原研900-04
LCZ696原料
LCZ697雜質(zhì)
LCZ696中間體5
AHU-377(鈉鹽)
沙庫(kù)必曲(AHU-377)
LCZ696中間體 10G
LCZ696原研900-04
AHU-377(LCZ696中間體)
AHU-77
AHU-377
Sacubitril(AHU-377)
(2R,4S)-5-([1,1'-Biphenyl]-4-yl)-4-(3-carboxypropanamido)-2-methylpentanoic acid
4-{[(2S,4R)-1-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl]amino}-4-oxobutanoic acid
(2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester
4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid
4-(((2S,4R)-1-([1,1'-Biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic a
4-(((2R,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-Methyl-5-oxopentan-2-yl)aMino)-4-oxobutanoic acid
物理化學(xué)性質(zhì)
常見(jiàn)問(wèn)題列表
該藥物臨床試驗(yàn)中，針對(duì)一個(gè)雙盲二期試驗(yàn)患者的輕度至中度高血壓，對(duì)其用于100至400毫克的劑量組合藥物，80至320毫克的纈沙坦，200毫克的neprilysin抑制劑或安慰劑。組合藥物的效果比僅與纈沙坦等藥物效果更為顯著，且耐受性良好，無(wú)血管性水腫的報(bào)告。LCZ696從治療早期便表現(xiàn)出了可持續(xù)的治療利益：
（1）心血管疾病死亡風(fēng)險(xiǎn)降低20%（p=0.00004）。
（2）心臟衰竭住院率降低21%（p=0.00004）。
（3）全因死亡風(fēng)險(xiǎn)降低16%（p=0.0005）。
（4）總體而言，綜合衡量心血管死亡或心臟衰竭住院主要終點(diǎn)，風(fēng)險(xiǎn)降低20%（p=0.0000002）。
LCZ696是一種結(jié)合了諾華的Diovan和正處于研究階段的AHU-377的藥物，一些分析人士也對(duì)這種藥物給予了很高評(píng)價(jià)并認(rèn)為諾華公司可能最早將于明年提交FDA審核，一旦獲得通過(guò)將使諾華公司在心血管藥物領(lǐng)域再下一城。
不過(guò)，盡管諾華公司對(duì)LCZ696表現(xiàn)出很高的期待。但是考慮到其serelaxin在FDA和歐盟醫(yī)藥管理部門(mén)的挫折，諾華公司還有很長(zhǎng)一段路要走。
The news came straight from Basel as investigators around the world were wrapping up the big scientific meeting of the American College of Cardiology.
IC50: 5 nM (NEP)
Sacubitril (AHU-377) is a single molecule that is comprised of molecular moieties of valsartan, an ARB, and Sacubitril (AHU-377), a neprilysin inhibitor (1:1 ratio). Sacubitril (AHU-377) is converted by enzymatic cleavage of the ethyl ester into the active neprilysin inhibiting metabolite LBQ657. The inactive NEPi precursor, Sacubitril (AHU-377), does not inhibit collagen accumulation in fibroblasts nor cardiac myocyte hypertrophy. In cardiac fibroblasts, the active NEPi LBQ657 had no discernible effects. In contrast, LBQ657 modestly inhibits cardiac myocyte hypertrophy.
In humans, Sacubitril (AHU-377) (t max 0.5-1.1 h) are absorbed quickly. Sacubitril (AHU-377) is converted rapidly into LBQ657 with its t max being reached in 1.9-3.5 h. Mean t 1/2 values for the biologically active LBQ657 is 9.9-11.1 h. In vehicle-treated dogs, ANF increases urinary sodium excretion from 17.3±3.6 to 199.5±18.4 pequivkglmin. This effect is potentiated significantly in animals which receive Sacubitril (AHU-377). Urinary volume is also potentiated in animals which receive an iv administration of Sacubitril (AHU-377).