マラビロック 化学特性,用途語,生産方法
効能
抗ウイルス薬, ケモカイン受容体5拮抗薬
商品名
シーエルセントリ (ヴィーブヘルスケア)
説明
Maraviroc is the first CCR5 receptor antagonist that has been developed and
launched for the treatment of HIV-1. Maraviroc binds in a slowly reversible,
allosteric manner to CCR5, which is one of two principle chemokine co-receptors
for viral entry into the host cell, the other being CXCR4. Binding of maraviroc to
CCR5 induces conformational changes within the chemokine receptor, thereby
preventing CCR5 binding to the viral gp120 protein and the ultimate CCR5-
mediated virus-cell fusion that is a prerequisite for HIV invasion. Maraviroc, with
its unique mechanism of action as a fusion inhibitor, joins the greater than 20
marketed antiretrovirals, including nucleotide reverse transcriptase inhibitors
(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and PIs. It is
approved for use in combination with these other antiretroviral drugs in adult
patients with R5-tropic HIV-1 infection (but not X4 or dual/mixed tropic HIV-1).
化学的特性
Brown Solid
使用
Maraviroc is a CCR5 antagonist for MIP-1α, MIP-1β and RANTES with IC50 of 3.3 nM, 7.2 nM and 5.2 nM, respectively
定義
ChEBI: A monocarboxylic acid amide obtained by formal condensation of the carboxy group of 4,4-difluorocyclohexanecarboxylic acid and the primary amino group of (1S)-3-[(3-exo)-3-(3-isopropyl-5-methyl-4H-1,2,4-
riazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropylamine. An antiretroviral drug, it prevents the interaction of HIV-1 gp120 and chemokine receptor 5 (CCR5) necessary for CCR5-tropic HIV-1 to enter cells.
獲得抵抗性
In most patients (c. 60%) failure of response is associated
with the selection of virus that can use CXCR4 as its entry
co-receptor. Evidence for the selection of virus that continues
to use CCR5 has also been described.
応用例（製薬）
A spirodiketopiperazine formulated as tablets for oral use.
薬物動態学
Oral absorption: c. 33% (300 mg dose)
C
max 150 mg twice daily: c. 332 μg/L*
C
min 150 mg twice daily: c. 101 μg/L*
Plasma half-life: c. 13.2 h (30 mg iv
administration)
Volume of distribution: c. 194 L
Plasma protein binding: c. 76%
Absorption
The absolute bioavailability of a 100 mg dose is 23% and is predicted to be 33% after a 300 mg dose. Co-administration of a 300 mg tablet and a high-fat meal has resulted in reduced C
max and AUC by 33% in healthy volunteers. However, because no food restrictions were enacted during clinical trials, maraviroc may be taken with or without food.
Distribution
Animal experiments suggest low CSF concentrations around 10% of free plasma concentrations. It is not known whether it passes into breast milk. A study of genital tract secretions and vaginal tissue in healthy HIV-uninfected female volunteers suggest a concentration in cervicovaginal fluid more than four-fold higher than that in plasma.
Metabolism
It is a substrate for CYP3A4 and P-glycoprotein, but does not appear to inhibit or induce CYP3A4.
Excretion
Seventy-six and 19% of a radiolabeled maraviroc dose were recovered in the feces and urine, respectively.
臨床応用
Treatment of HIV infection (in combination with other antiretroviral drugs)
in treatment-experienced patients
On November 20, 2009, the US Food and Drug Administration approved
a supplemental new drug application to expand the indication for
maraviroc to include combination antiretroviral treatment of treatmentnaive
adults infected with CCR5-tropic HIV virus
副作用
Overall, maraviroc was well tolerated with the most common adverse events being cough, fever, colds, rash, muscle and joint pain, stomach pain, and dizziness. While some patients did experience liver enzyme elevation, these events did not appear to be doserelated. Since hepatotoxicity did occur in one patient with prior liver function abnormalities, maraviroc s label warns of a potentially increased risk of hepatoxicity with treatment. Postural hypotension was also observed in a dosedependent manner; however, no patients discontinued therapy as a result. As a substrate for CYP3A4, the dose of maraviroc should be reduced by 50% in the presence of strong CYP3A4 inhibitors. Conversely, concomitant use of strong CYP3A4 inducers requires a 50% increase in maraviroc dose. While there are no contraindications, maraviroc should be used with caution in patients with liver dysfunction, high risk of cardiovascular events, and pre-existing postural hypotension.
マラビロック 上流と下流の製品情報
原材料
8-(フェニルメチル)-8-アザビシクロ[3.2.1]オクタン-3-オン
(1S)-3-[3-(3-イソプロピル-5-メチル-4H-1,2,4-トリアゾール-4-イル)-EXO-8-アザビシクロ[3.2.1]オクト-8-イル]-1-フェニル-1-プロパンアミン
4,4-ジフルオロシクロヘキサンカルボン酸
4,4-DIFLUORO-N-((1S)-3-OXO-1-PHENYLPROPYL)CYCLOHEXANE-1-CARBOXAMIDE
8-ベンジル-3-(3-イソプロピル-5-メチル-4H-1,2,4-トリアゾール-4-イル)-EXO-8-アザビシクロ[3.2.1]オクタン
(3S)-3-アミノ-3-フェニルプロパン酸メチル
N-BOC-(3S)-3-フェニル-3-アミノプロピオンアルデヒド
(1R,3S,5S)-3-(3-ISOPROPYL-5-METHYL-4H-1,2,4-TRIAZOL-4-YL)-8-AZABICYCLO[3.2.1]OCTANE
((S)-3-[3-(3-ISOPROPYL-5-METHYL-[1,2,4]TRIAZOL-4-YL)-8-AZA-BICYCLO[3.2.1]OCT-8-YL]-1-PHENYL-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER
4,4-ジフルオロシクロヘキサン-1-カルボニルクロリド
4-メチルベンゼンスルホン酸3-(3-イソプロピル-5-メチル-4H-1,2,4-トリアゾール-4-イル)-8-アザビシクロ[3.2.1]オクタン
4,4-ジフルオロシクロヘキサンジカルボン酸エチル
(3S)-3-BOC-アミノ-3-フェニルプロピオン酸メチル
準備製品