印地那韦
描述
印地那韦，商品名为克立芝，是一种蛋白酶抑制剂，用作高度活性的抗逆转录病毒疗法的一部分，用于治疗 HIV/AIDS 。它是一种白色可溶性粉末，以口服的方式与其他抗病毒药物联合使用。 印地那韦是人工合成的，用于抑制 HIV 病毒中的蛋白酶，阻止病毒复制，从而降低患者体内的病毒载量 .
科学研究应用
Antiretroviral Therapy
Indinavir in Combination Therapy
Indinavir is most recognized for its role in combination antiretroviral therapy (cART) for HIV. In clinical trials, such as the AIDS Clinical Trial Group study 320, indinavir combined with nucleoside reverse transcriptase inhibitors (NRTIs) demonstrated significant efficacy in slowing disease progression and improving quality of life among patients with advanced HIV infection. The study involved 1,156 protease inhibitor- and lamivudine-naive patients, revealing that the triple-drug regimen resulted in a 50% reduction in the risk of progression to AIDS or death compared to dual NRTI therapy alone .
Metabolic Effects
Impact on Glucose Metabolism
Research indicates that indinavir can acutely inhibit insulin-stimulated glucose disposal. A study utilizing a euglycemic hyperinsulinemic clamp showed that indinavir decreased glucose uptake by interfering with the insulin-regulated glucose transporter GLUT-4. This effect was observed at therapeutic concentrations, suggesting a direct impact on glucose metabolism that could contribute to metabolic complications in HIV patients receiving protease inhibitors .
| Parameter | Before Indinavir | After Indinavir |
|---|---|---|
| Glucose Uptake (µmol/kg/min) | Baseline Value | Decreased by 26% |
| Insulin Levels (pmol/L) | Steady State | Maintained at ~400 |
Pharmacokinetics and Bioequivalence Studies
Indinavir's pharmacokinetics have been extensively studied to optimize dosing regimens and assess bioequivalence between formulations. A high-performance liquid chromatography (HPLC) method was developed for quantifying indinavir levels in human plasma, demonstrating high sensitivity and specificity. This method has been applied in bioequivalence studies to compare new generic formulations against reference products, ensuring therapeutic equivalence .
| Parameter | Reference Product | Generic Product |
|---|---|---|
| Cmax (µg/mL) | X | Y |
| AUC0-t (µg·h/mL) | X | Y |
| Bioequivalence Range (%) | 0.80 - 1.25 | Achieved |
Research on Cancer Therapeutics
Recent investigations have explored the potential repurposing of indinavir as an anticancer agent, particularly targeting survivin, a protein implicated in cancer cell survival. Although initial studies suggested no direct binding of indinavir to survivin, the compound's role in modulating cellular pathways warrants further exploration into its potential applications in oncology .
作用机制
印地那韦抑制 HIV 病毒蛋白酶，这对于将病毒多蛋白前体蛋白水解成单个功能性蛋白质至关重要。通过与蛋白酶活性位点结合，印地那韦阻止了这些多蛋白的切割，导致形成不成熟的、不可感染的病毒颗粒。 这种抑制降低了患者的病毒载量，减缓了 HIV/AIDS 的进展 .
类似化合物：
- 利托那韦
- 沙奎那韦
- 奈非那韦
- 洛匹那韦
比较： 印地那韦在蛋白酶抑制剂中是独特的，因为它具有特定的结合亲和力和抑制机制。虽然其他蛋白酶抑制剂如利托那韦和沙奎那韦也靶向 HIV 蛋白酶，但印地那韦的分子结构允许其与酶的活性位点发生不同的相互作用，从而导致不同的药代动力学和药效学特征。 此外，印地那韦的溶解度和生物利用度通过其特定的化学修饰得到增强 .
尽管印地那韦存在副作用，并且在某些情况下会产生耐药性，但其独特的性质使其成为治疗 HIV/AIDS 的宝贵工具。 与其他蛋白酶抑制剂的比较突出了在开发有效的抗逆转录病毒疗法中结构多样性的重要性 .
生化分析
Biochemical Properties
Indinavir interacts with HIV-1 protease, an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1 . The interaction between Indinavir and HIV-1 protease inhibits the activity of the enzyme .
Cellular Effects
Indinavir influences cell function by preventing the cleavage of the viral polyproteins, resulting in the formation of immature non-infectious viral particles . This impacts cell signaling pathways, gene expression, and cellular metabolism.
Molecular Mechanism
Indinavir exerts its effects at the molecular level by binding to the protease active site, inhibiting the enzyme’s activity . This inhibition prevents the cleavage of the viral polyproteins, leading to the formation of immature non-infectious viral particles .
Temporal Effects in Laboratory Settings
It is known that Indinavir is a potent and specific HIV protease inhibitor .
Metabolic Pathways
Indinavir is metabolized in the body, with seven metabolites identified, one glucuronide conjugate and six oxidative metabolites . Cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for the formation of these oxidative metabolites .
准备方法
合成路线和反应条件： 印地那韦通过多步合成过程合成，涉及形成多个中间体反应条件通常涉及使用有机溶剂、催化剂和控制温度，以确保所需的化学转化高效地发生 .
工业生产方法： 印地那韦的工业生产涉及使用优化的反应条件进行大规模合成，以最大限度地提高产量和纯度。该过程包括严格的纯化步骤，例如结晶和色谱，以获得纯净形式的最终产品。 生产是在严格的质量控制措施下进行的，以确保一致性和安全性 .
化学反应分析
反应类型： 印地那韦经历各种化学反应，包括：
氧化： 印地那韦在特定条件下可以被氧化，导致形成氧化衍生物。
还原： 还原反应可以改变印地那韦中的官能团，可能改变其活性。
常用试剂和条件：
氧化： 常见的氧化剂包括过氧化氢和高锰酸钾。
还原： 使用硼氢化钠和氢化铝锂等还原剂。
主要形成的产物： 由这些反应形成的主要产物取决于所使用的特定试剂和条件。 例如，氧化会导致形成羟基化或酮类衍生物，而还原会导致形成醇或胺 .
相似化合物的比较
- Ritonavir
- Saquinavir
- Nelfinavir
- Lopinavir
Comparison: Indinavir is unique among protease inhibitors due to its specific binding affinity and inhibition mechanism. While other protease inhibitors like ritonavir and saquinavir also target the HIV protease enzyme, indinavir’s molecular structure allows for distinct interactions with the enzyme’s active site, leading to different pharmacokinetic and pharmacodynamic profiles. Additionally, indinavir’s solubility and bioavailability are enhanced by its specific chemical modifications .
Indinavir’s unique properties make it a valuable tool in the treatment of HIV/AIDS, despite its side effects and the development of resistance in some cases. Its comparison with other protease inhibitors highlights the importance of structural diversity in developing effective antiretroviral therapies .
生物活性
Indinavir is a potent protease inhibitor used primarily in the treatment of Human Immunodeficiency Virus (HIV) infection. Its mechanism of action involves inhibiting the HIV-1 protease enzyme, which is crucial for the maturation of infectious viral particles. This article reviews the biological activity of indinavir, including its pharmacodynamics, clinical efficacy, side effects, and case studies that highlight its therapeutic applications.
Indinavir specifically targets the HIV-1 protease enzyme, preventing the cleavage of polyproteins into functional proteins necessary for viral replication. By binding to the active site of the protease, indinavir inhibits the formation of mature and infectious virions, thereby reducing viral load in infected individuals. The inhibitory concentration (IC50) for indinavir is approximately 50-100 nM in cell culture models .
Pharmacokinetics
Indinavir exhibits rapid absorption when administered orally, with peak plasma concentrations occurring approximately 0.8 hours post-dose . The pharmacokinetic profile shows nonlinear characteristics due to dose-dependent metabolism. Renal clearance slightly exceeds glomerular filtration rate, indicating a net tubular secretion component .
Table 1: Pharmacokinetic Properties of Indinavir
| Property | Value |
|---|---|
| Absorption | Rapid (Tmax ~0.8 h) |
| Protein Binding | ~60% |
| Renal Clearance | Exceeds glomerular filtration |
| IC50 | 50-100 nM |
Clinical Efficacy
Indinavir has demonstrated significant clinical efficacy in reducing HIV viral load and improving immune function in patients. A study involving patients with Kaposi's sarcoma (KS) showed that combining indinavir with chemotherapy resulted in a 75% overall response rate during maintenance therapy . In patients with early-stage KS, the response rate was even higher at 75%, compared to 50% in late-stage patients.
Case Study: Indinavir in Kaposi's Sarcoma Treatment
- Study Design : A phase II trial assessed indinavir's efficacy in combination with vinblastine and bleomycin.
- Participants : Patients with advanced progressive KS.
- Results :
- Overall response rate: 75%
- Median response duration: 43 months
- Immune status improvement noted.
Side Effects and Safety Profile
Despite its therapeutic benefits, indinavir is associated with several side effects, particularly renal complications. A retrospective cohort study reported an incidence of indinavir-associated renal complications (IRC) at 7.3%, with symptoms including loin pain and renal colic . The study indicated that prolonged exposure to indinavir (>74 weeks) reduced the risk of IRC.
Table 2: Incidence of Indinavir-Associated Renal Complications
| Complication Type | Incidence (%) |
|---|---|
| Loin Pain | 58 |
| Renal Colic | 42 |
| Dysuria | 19 |
Insulin Resistance
Research has shown that indinavir can induce insulin resistance, leading to impaired glucose tolerance in patients. A study found that a single dose of indinavir decreased insulin-stimulated glucose disposal by approximately 34% in healthy volunteers . This effect poses a risk for developing type II diabetes among long-term users.
属性
IUPAC Name |
(2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C36H47N5O4/c1-36(2,3)39-35(45)31-24-40(22-26-12-9-15-37-21-26)16-17-41(31)23-29(42)19-28(18-25-10-5-4-6-11-25)34(44)38-33-30-14-8-7-13-27(30)20-32(33)43/h4-15,21,28-29,31-33,42-43H,16-20,22-24H2,1-3H3,(H,38,44)(H,39,45)/t28-,29+,31+,32-,33+/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
CBVCZFGXHXORBI-PXQQMZJSSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)(C)NC(=O)C1CN(CCN1CC(CC(CC2=CC=CC=C2)C(=O)NC3C(CC4=CC=CC=C34)O)O)CC5=CN=CC=C5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC(C)(C)NC(=O)[C@@H]1CN(CCN1C[C@H](C[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H]3[C@@H](CC4=CC=CC=C34)O)O)CC5=CN=CC=C5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C36H47N5O4 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
157810-81-6 (sulfate (1:1) (salt)) |
Source
|
| Record name | Indinavir [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0150378179 | |
| 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. | |
DSSTOX Substance ID |
DTXSID4043802 |
Source
|
| Record name | Indinavir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4043802 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
613.8 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Indinavir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014369 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
4.82e-02 g/L |
Source
|
| Record name | Indinavir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00224 | |
| 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 | Indinavir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014369 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Indinavir inhibits the HIV viral protease enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles. |
Source
|
| Record name | Indinavir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00224 | |
| 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. |
150378-17-9 |
Source
|
| Record name | Indinavir | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=150378-17-9 | |
| 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 | Indinavir [USAN:INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0150378179 | |
| 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 | Indinavir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00224 | |
| 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 | Indinavir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4043802 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | INDINAVIR ANHYDROUS | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/9MG78X43ZT | |
| 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. | |
| Record name | Indinavir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014369 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
167.5-168 °C, 167.5 - 168 °C |
Source
|
| Record name | Indinavir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00224 | |
| 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 | Indinavir | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014369 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
体外研究产品的免责声明和信息
请注意，BenchChem 上展示的所有文章和产品信息仅供信息参考。 BenchChem 上可购买的产品专为体外研究设计，这些研究在生物体外进行。体外研究，源自拉丁语 "in glass"，涉及在受控实验室环境中使用细胞或组织进行的实验。重要的是要注意，这些产品没有被归类为药物或药品，他们没有得到 FDA 的批准，用于预防、治疗或治愈任何医疗状况、疾病或疾病。我们必须强调，将这些产品以任何形式引入人类或动物的身体都是法律严格禁止的。遵守这些指南对确保研究和实验的法律和道德标准的符合性至关重要。
