ビクリビロックは、CCR5受容体の非競合的アロステリックアンタゴニストとして機能します。これは、CCR5受容体の細胞外表面に近い膜貫通ヘリックス間に位置する疎水性ポケットに結合します。この結合により、受容体のコンフォメーションが変化し、HIV-1 gp120タンパク質がCCR5に結合することができなくなります。その結果、HIV-1が宿主細胞に侵入することが阻害され、ウイルスのライフサイクルの初期段階が阻止されます .

準備方法

合成経路と反応条件

ビクリビロックの合成は、重要な中間体の調製から始まり、複数のステップが含まれています温度、溶媒、触媒などの特定の反応条件は、高収率と純度を確保するために最適化されています .

工業生産方法

ビクリビロックの工業生産は、同様の合成経路に従いますが、商業的な需要を満たすために規模が拡大されています。このプロセスには、規制基準への適合性と一貫性を確保するための厳格な品質管理対策が含まれています。連続フロー化学や自動合成などの高度な技術が、効率の向上と生産コストの削減に役立つ場合があります .

化学反応の分析

反応の種類

ビクリビロックは、次のようなさまざまな化学反応を起こします。

酸化： ビクリビロックは酸化されて、主要な代謝産物であるビクリビロックN-オキシドを形成する可能性があります.

還元： 還元反応は、分子内の特定の官能基を修飾するために使用できます。

置換： 置換反応は、ピリミジンコアに置換基を導入または置換するために使用できます.

一般的な試薬と条件

これらの反応で使用される一般的な試薬には、酸化のためのシトクロムP450酵素などの酸化剤、還元のための還元剤、置換反応のための求核剤が含まれます。温度、pH、溶媒の選択などの反応条件は、所望の結果を得るために注意深く制御されます .

生成される主要な生成物

これらの反応によって生成される主要な生成物には、this compoundN-オキシドと、母体化合物の修飾によって生じる他の代謝産物が含まれます .

類似化合物との比較

ビクリビロックは、CCR5阻害剤として知られる化合物のクラスの一部です。類似の化合物には以下が含まれます。

マラビロック： HIV-1感染の治療における臨床使用が承認されている別のCCR5阻害剤.

アプラビロック： 肝毒性の懸念により中止されたCCR5阻害剤.

INCB009471： 臨床開発中のCCR5阻害剤.

TBR 652： 調査中の別のCCR5阻害剤.

ビクリビロックは、さまざまなHIVサブタイプに対して強力なin vitro活性と、良好な薬物動態および薬力学特性を持つことで、ユニークです。特に治療歴のある患者において、臨床試験で有望な結果が示されています .

特性

IUPAC Name	(4,6-dimethylpyrimidin-5-yl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl]methanone	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI	InChI=1S/C28H38F3N5O2/c1-19-16-35(14-15-36(19)24(17-38-5)22-6-8-23(9-7-22)28(29,30)31)27(4)10-12-34(13-11-27)26(37)25-20(2)32-18-33-21(25)3/h6-9,18-19,24H,10-17H2,1-5H3/t19-,24-/m0/s1	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

InChI Key	CNPVJJQCETWNEU-CYFREDJKSA-N	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Canonical SMILES	CC1CN(CCN1C(COC)C2=CC=C(C=C2)C(F)(F)F)C3(CCN(CC3)C(=O)C4=C(N=CN=C4C)C)C	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Isomeric SMILES	C[C@H]1CN(CCN1[C@@H](COC)C2=CC=C(C=C2)C(F)(F)F)C3(CCN(CC3)C(=O)C4=C(N=CN=C4C)C)C	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Molecular Formula	C28H38F3N5O2	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

DSSTOX Substance ID	DTXSID40897719	Source
Record name	Vicriviroc
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID40897719
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Molecular Weight	533.6 g/mol	Source
Source	PubChem
URL	https://pubchem.ncbi.nlm.nih.gov
Description	Data deposited in or computed by PubChem

Mechanism of Action	Vicriviroc is a once daily oral inhibitor of CCR5. It noncompetitively binds to a hydrophobic pocket between transmembrance helices by the extracellular side of CCR5. This allosteric antagonism causes a conformational change in the protein preventing binding of gp120 to CCR5. This prevents the entry of HIV into the cell.	Source
Record name	Vicriviroc
Source	DrugBank
URL	https://www.drugbank.ca/drugs/DB06652
Description	The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation	Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

CAS No.	306296-47-9, 394730-30-4	Source
Record name	Vicriviroc
Source	CAS Common Chemistry
URL	https://commonchemistry.cas.org/detail?cas_rn=306296-47-9
Description	CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society.
Explanation	The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.

Record name	Vicriviroc [INN]
Source	ChemIDplus
URL	https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0306296479
Description	ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system.

Record name	SCH-D (Old RN)
Source	ChemIDplus
URL	https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0394730304
Description	ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system.

Record name	Vicriviroc
Source	DrugBank
URL	https://www.drugbank.ca/drugs/DB06652
Description	The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
Explanation	Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)

Record name	Vicriviroc
Source	EPA DSSTox
URL	https://comptox.epa.gov/dashboard/DTXSID40897719
Description	DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.

Record name	VICRIVIROC
Source	FDA Global Substance Registration System (GSRS)
URL	https://gsrs.ncats.nih.gov/ginas/app/beta/substances/TL515DW4QS
Description	The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions.
Explanation	Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.

Customer

Q & A

A: Vicriviroc is a CCR5 antagonist, meaning it binds to the CCR5 receptor on the surface of CD4+ cells []. By doing so, it blocks the interaction between the HIV-1 envelope glycoprotein gp120 and CCR5, preventing viral entry into the cell [, , ].

A: The primary downstream effect is the inhibition of HIV-1 replication by preventing viral entry [, ]. Blocking CCR5 also inhibits the signaling cascade typically initiated by chemokine binding, potentially affecting immune cell migration and activation [, ].

A: The molecular formula of Vicriviroc is C27H39F3N6O2. Its molecular weight is 536.63 g/mol [].

A: Yes, studies have utilized various spectroscopic techniques to characterize Vicriviroc, including NMR spectroscopy and X-ray analysis. These studies have provided insights into the 3D properties and conformational behavior of the molecule, particularly concerning the arrangement at the planar amido function and the conformational preferences of the piperazine and piperidine rings [].

ANone: The provided research focuses primarily on Vicriviroc's biological activity and pharmacological properties. Therefore, detailed information regarding material compatibility and stability under various conditions is limited within these studies.

A: Vicriviroc acts as a receptor antagonist and does not exhibit catalytic properties []. Its primary mechanism involves competitive binding to the CCR5 receptor, inhibiting HIV-1 entry.

A: Yes, computational chemistry and modeling have been employed to understand the interactions of Vicriviroc with the CCR5 receptor []. Models have been developed to simulate the binding of Vicriviroc to the transmembrane domain of CCR5 and analyze its impact on receptor conformation and interaction with HIV-1 gp120 [].

A: Research has shown that even single amino acid substitutions in the V3 loop region of the HIV-1 envelope glycoprotein gp120 can significantly impact Vicriviroc resistance []. Specific mutations, such as K305R and K319T, have been linked to altered resistance and infectivity profiles [].

A: While specific stability data is limited within the provided research, it is known that Vicriviroc is metabolized primarily by the CYP3A4 enzyme system [, ]. Co-administration with CYP3A4 inhibitors or inducers may necessitate dose adjustments []. Formulation strategies, such as the development of intravaginal rings, have been explored to achieve sustained drug delivery and potentially improve bioavailability [].

ANone: The research primarily focuses on the scientific and clinical aspects of Vicriviroc. Detailed information regarding specific SHE regulations and compliance is not extensively discussed.

A: Vicriviroc exhibits good oral bioavailability and a long half-life, permitting once-daily dosing [, , , ]. It is primarily metabolized by the CYP3A4 enzyme system, necessitating dose adjustments when co-administered with CYP3A4 inhibitors or inducers [, , , ]. Studies in humans, monkeys, and rats reveal that the drug is metabolized through O-demethylation, N-dealkylation, oxidation, and glucuronidation [].

A: Studies have shown a correlation between higher Vicriviroc concentrations, particularly the minimum plasma concentration (Cmin), and a greater decrease in HIV-1 RNA levels []. Subjects with a Cmin above 54 ng/mL exhibited a significantly larger mean decrease in viral load compared to those with a lower Cmin []. This correlation suggests a concentration-dependent antiviral effect of Vicriviroc.

A: Yes, Vicriviroc has demonstrated potent antiviral activity in both in vitro and in vivo studies. In vitro, it effectively inhibits the replication of various HIV-1 isolates, including drug-resistant strains, and exhibits synergistic effects with other antiretroviral agents []. In clinical trials, Vicriviroc, when administered with a boosted protease inhibitor-containing regimen, significantly reduced HIV-1 RNA levels in treatment-experienced patients compared to placebo, with sustained efficacy observed over 48 weeks []. Furthermore, studies have explored its potential in treatment-naïve patients [, ].

A: Resistance to Vicriviroc primarily arises from mutations within the HIV-1 envelope glycoprotein, specifically the V3 loop region [, , , ]. These mutations can reduce the binding affinity of Vicriviroc to CCR5, thereby diminishing its antiviral activity.

A: Cross-resistance to other CCR5 antagonists, such as TAK-779, has been reported in HIV-1 isolates with reduced susceptibility to Vicriviroc []. This suggests that mutations conferring resistance to one CCR5 antagonist might confer resistance to others within the same class.

A: Research has investigated intravaginal rings containing Vicriviroc and MK-2048, a novel nucleoside reverse transcriptase translocation inhibitor, for sustained drug delivery to prevent HIV-1 infection []. This approach aims to achieve high drug concentrations in the vaginal mucosa while minimizing systemic exposure.

A: Liquid chromatography coupled with mass spectrometry (LC-MS) is a primary method used to identify and quantify Vicriviroc and its metabolites in biological samples []. This technique provides high sensitivity and selectivity for analyzing drug concentrations in various matrices.

ANone: The provided research focuses primarily on Vicriviroc's biological activity, pharmacology, and clinical effects. Therefore, information regarding environmental impact, dissolution/solubility, analytical method validation, alternatives, recycling/waste management, research infrastructure/resources, and related aspects is limited within these studies.

ANone: Vicriviroc emerged as part of the research effort to develop new antiretroviral therapies, specifically targeting the HIV-1 entry process. It represents a second-generation CCR5 antagonist, building upon earlier research on compounds like SCH-C. Despite its initial promise, Vicriviroc faced challenges in phase III clinical trials, leading to the discontinuation of its development as a treatment for HIV-1 infection. Nevertheless, the knowledge gained from Vicriviroc research has contributed to the understanding of HIV-1 entry mechanisms and the development of other antiretroviral drugs.

A: While the primary focus of Vicriviroc research has been on HIV-1 treatment, the knowledge gained has broader implications. For instance, understanding the role of CCR5 in viral entry and the mechanisms of CCR5 antagonist action can inform research on other viruses that utilize this receptor, such as some flaviviruses []. Additionally, Vicriviroc's effects on CCR5 signaling and immune cell migration could have implications for understanding and potentially treating inflammatory and autoimmune diseases.

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BenchChemで提示されるすべての記事および製品情報は、情報提供を目的としています。BenchChemで購入可能な製品は、生体外研究のために特別に設計されています。生体外研究は、ラテン語の "in glass" に由来し、生物体の外で行われる実験を指します。これらの製品は医薬品または薬として分類されておらず、FDAから任何の医療状態、病気、または疾患の予防、治療、または治癒のために承認されていません。これらの製品を人間または動物に体内に導入する形態は、法律により厳格に禁止されています。これらのガイドラインに従うことは、研究と実験において法的および倫理的な基準の遵守を確実にするために重要です。

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