About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma.
Amount of absorbed dose that undergoes metabolism not established; however, drug appears to undergo minimal hepatic metabolism. CYP isoenzyme 3A4 appears to be main enzyme responsible for metabolism of drug based on in vitro studies. Also, a substrate for p-glycoprotein.
The major metabolic pathways for aliskiren were O-demethylation at the phenyl-propoxy side chain or 3-methoxy-propoxy group, with further oxidation to the carboxylic acid derivative.
来源:Hazardous Substances Data Bank (HSDB)
代谢
... 阿利吉仑的两个主要氧化代谢物在达到最高浓度时在血浆中的药物含量不超过5%。 ...
... The two major oxidized metabolites of aliskiren account for less than 5% of the drug in the plasma at the time of the maximum concentration. ...
Serum aminotransferase elevations during aliskiren therapy are uncommon and rates of such elevations have not been reported in the large clinical trials that demonstrated its efficacy in hypertension. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of aliskiren and several instances of marked serum enzyme elevations during therapy with few symptoms and without jaundice have been reported. In most instances, the pattern of enzyme elevation was distinctly hepatocellular and recovery was prompt once aliskiren was stopped. There have also been reports to the sponsor of severe hepatic reactions including hepatic failure and more recently a published case report of acute liver injury attributed to this agent. The latency to onset has ranged from 1 to 6 months and the pattern of injuryis typically cholestatic or mixed. Most cases have been mild to moderate in severity and marked by rapid recovery once aliskiren is stopped.
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration.
Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route.
来源:DrugBank
吸收、分配和排泄
分布容积
未改变的阿利吉仑大约占血浆中药物总量的80%。
Unchanged aliskiren accounts for about 80% of the drug found in the plasma.
Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers.
来源:DrugBank
吸收、分配和排泄
吸收不良；口服生物利用度约为2.5%。
Poorly absorbed; oral bioavailability is about 2.5%.
[EN] A NOVEL PROCESS FOR MAKING ALISKIREN, ITS NOVEL INTERMEDIATES AND CERTAIN NOVEL COMPOUNDS [FR] NOUVEAU PROCÉDÉ DE PRODUCTION D'ALISKIRÈNE, SES NOUVEAUX INTERMÉDIAIRES ET CERTAINS NOUVEAUX COMPOSÉS
[EN] A PROCESS FOR THE PREPARATION OF INTERMEDIATES USEFUL IN THE PRODUCTION OF ALISKIREN<br/>[FR] PROCÉDÉ DE PRÉPARATION D'INTERMÉDIAIRES UTILES DANS LA PRODUCTION DE L'ALISKIREN
申请人：WATSON LAB INC
公开号：WO2012078147A1
公开（公告）日：2012-06-14
A process for preparing 4-[(2R)-2-X-methyl)-3-methylbutyl]-1 -methoxy-2-3(3- methoxypropoxy)-benzene wherein X is a leaving group and use of this compound in the synthesis of aliskiren.
[EN] ANGIOTENSIN II RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DES RÉCEPTEURS DE L'ANGIOTENSINE II
申请人：NICOX SA
公开号：WO2010015447A1
公开（公告）日：2010-02-11
A compound having the structure (formula 1) wherein R is a "sartan family" moiety Z is a nitroxy carrying moiety, or a pharmaceutically acceptable salt thereof. The compounds are active against hypertension.
A compound having the structure
wherein
X is selected from the group consisting of:
a bond, —NHCH
2
(CH
2
)
n
CH
2
OC(O)—, —CH
2
NHC(O)CH
2
NHC(O)—, —CH
2
OC(O)—, —OCH(CH
3
)OC(O)—, —OCH
2
OC(O)—,
—O—, —NR
1
—, —CR
1
R
3
—, —(CH
2
)
p
—, —(CH
2
)
q
NR
1
C(O)—, —CHR
5
NR
2
C(O)—, —(CH
2
)
q
C(O)—, —(CH
2
)
q
C(O)—, —(CH
2
)
q
C(O)NR
1
—,
or a pharmaceutically acceptable salt thereof, and methods of using the compounds for treating, hypertension.
Disclosed are δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compounds of formula (I)
and the salts thereof, having renin-inhibiting properties. Also disclosed are pharmaceutical compositions comprising these compounds and methods of administering them for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.
CYCLIC TETRAMER COMPOUNDS AS PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) INHIBITORS FOR THE TREATMENT OF METABOLIC DISORDERS
申请人：NOVARTIS AG
公开号：US20200164024A1
公开（公告）日：2020-05-28
The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R
1
, R
1
, R
1
, R
1
, R
1
, R
1
, R
1
, R
1
, R
1
, X
1
, X
2
, and X
3
are described herein.
