アピキサバン 化学特性,用途語,生産方法
用途
アピキサバン（Apixaban、開発コードBMS-562247-01）は、血栓塞栓症の治療?予防に用いられる、経口投与が可能な抗凝固剤の1つである。商品名エリキュース。血液凝固因子の1種であるXa因子を薬剤そのものが阻害する、直接Xa因子阻害薬（英語版）に分類される。また、第Xa因子は酵素なので、酵素阻害剤に分類される薬剤でもある。なお、肝代謝型（肝排泄型）の薬剤としても知られる。
効能
抗凝固薬, 抗血栓薬, 第Xa因子阻害薬
商品名
エリキュース (ブリストル・マイヤーズスクイブ)
説明
Eliquis (apixaban), a direct inhibitor of factor Xa (FXa), was approved by
the European Commission on May 18, 2011 for prevention of venous thromboembolic
events (VTE) in adult patients who have undergone elective hip or
knee replacement surgery.
The discovery of apixaban was the culmination of a succession of novel and innovative medicinal
chemistry discoveries starting with the identification of nonpeptide
leads, rational drug design using computer-aided and X-ray
crystallographic information, and the building of drug-like properties
through the systematic replacement of basic groups with neutral
moieties. Apixaban arose from modifications to razaxaban by constraining a pyrazole amide to form a
bicyclic pyrazolo-pyridinone scaffold. Optimization of the P1 group
resulted in the identification of the nonbasic methoxy phenyl group,
while a P4 piperidinone improved the balance of potency and
pharmacokinetics with low Vdss. The synthesis of apixaban begins with
the generation of a hydrazone of 4-methoxyaniline which is then used in
a 3+2 cycloaddition with a dihydropiperidinone to form a bicyclic
pyrazolo-pyridinone scaffold. The distal piperidinone group is installed
using an Ullmann coupling reaction followed by aminolysis of an ethyl
ester on the pyrazole ring to complete the synthesis of apixaban.
使用
Apixaban is a highly selective, reversible inhibitor of Factor Xa with Ki of 0.08 nM and 0.17 nM in human and rabbit, respectively.
定義
ChEBI: A pyrazolopyridine that is 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide substituted at position 1 by a 4-methoxyphenyl group and at position 6 by a 4-(2-oxopiperidin-1-yl)phenyl group. It is used for the
prevention and treatment of thromboembolic diseases.
薬物動態学
The maximum plasma concentration (Cmax) of apixaban occurs 3–4 h after oral administration. The absorption of apixaban appears to occur primarily in the small intestine and decreases progressively throughout the gastrointestinal tract. Compared with oral administration, the bioavailability of 2.5 mg of apixaban solution was approximately 60% and 84% lower when released in the distal small bowel and ascending colon, respectively. For oral doses up to 10 mg, the absolute bioavailability of apixaban is~50%, resulting from the incomplete absorption and first-pass metabolism in the gut and liver[1].
臨床応用
Apixaban is an oral anticoagulant with highly selective inhibition
of factor Xa. It was approved by the European Medicines
Agency (EMA) for the treatment of venous thromboembolic events
and first marketed in Germany under the brand name Eliquis in
June 2011. Apixaban was co-developed by Bristol-Myers Squibb
and Pfizer and represents the first approved drug for this indication
since warfarin over 50 years ago.
副作用
Possible side effects of Apixaban are: bleeding gums, nosebleeds, heavy vaginal bleeding
, red, pink, or brown urine; red or black, tarry stools; coughing or spitting up blood or a substance that looks like coffee grounds; swelling or joint pain, headache, rash, chest pain or tightness in the chest, swelling of the face or tongue, trouble breathing, wheezing. Feeling dizzy or fainting.Apixaban prevents your blood from clotting properly, so if you get a cut or injury, it may take longer than usual for the bleeding to stop. This medication may also cause you to bruise or bleed more easily.
参考文献
https://en.wikipedia.org/wiki/Apixaban
https://www.drugbank.ca/drugs/DB06605[1] Wonkyung Byon. “Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review.” Clinical Pharmacokinetics 58 10 (2019): 1265–1279.
アピキサバン 上流と下流の製品情報
原材料
準備製品