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Indinavir
Descripción general
Descripción
Indinavir, conocido por su nombre comercial Crixivan, es un inhibidor de la proteasa utilizado como componente de la terapia antirretroviral de alta actividad para tratar el VIH/SIDA . Es un polvo blanco, soluble, que se administra por vía oral en combinación con otros fármacos antivirales. This compound fue producido sintéticamente para inhibir la enzima proteasa del virus VIH, evitando que el virus se reproduzca y, por lo tanto, reduciendo la carga viral en los pacientes .
Aplicaciones Científicas De Investigación
Antiretroviral Therapy
Indinavir in Combination Therapy
This compound 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, this compound 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 this compound can acutely inhibit insulin-stimulated glucose disposal. A study utilizing a euglycemic hyperinsulinemic clamp showed that this compound 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 this compound | After this compound |
---|---|---|
Glucose Uptake (µmol/kg/min) | Baseline Value | Decreased by 26% |
Insulin Levels (pmol/L) | Steady State | Maintained at ~400 |
Pharmacokinetics and Bioequivalence Studies
This compound'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 this compound 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 this compound as an anticancer agent, particularly targeting survivin, a protein implicated in cancer cell survival. Although initial studies suggested no direct binding of this compound to survivin, the compound's role in modulating cellular pathways warrants further exploration into its potential applications in oncology .
Mecanismo De Acción
Indinavir inhibe la enzima proteasa viral del VIH, que es esencial para la escisión proteolítica de los precursores de poliproteínas virales en proteínas funcionales individuales. Al unirse al sitio activo de la proteasa, this compound evita la escisión de estas poliproteínas, lo que da como resultado la formación de partículas virales inmaduras y no infecciosas. Esta inhibición reduce la carga viral en los pacientes y ralentiza la progresión del VIH/SIDA .
Compuestos Similares:
- Ritonavir
- Saquinavir
- Nelfinavir
- Lopinavir
Comparación: this compound es único entre los inhibidores de proteasas debido a su afinidad de unión específica y su mecanismo de inhibición. Si bien otros inhibidores de proteasas como el ritonavir y el saquinavir también se dirigen a la enzima proteasa del VIH, la estructura molecular de this compound permite interacciones distintas con el sitio activo de la enzima, lo que lleva a diferentes perfiles farmacocinéticos y farmacodinámicos. Además, la solubilidad y la biodisponibilidad de this compound se mejoran mediante sus modificaciones químicas específicas .
Las propiedades únicas de this compound lo convierten en una herramienta valiosa en el tratamiento del VIH/SIDA, a pesar de sus efectos secundarios y el desarrollo de resistencia en algunos casos. Su comparación con otros inhibidores de proteasas pone de manifiesto la importancia de la diversidad estructural en el desarrollo de terapias antirretrovirales efectivas .
Análisis Bioquímico
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 this compound and HIV-1 protease inhibits the activity of the enzyme .
Cellular Effects
This compound 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
This compound 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 this compound is a potent and specific HIV protease inhibitor .
Metabolic Pathways
This compound 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 .
Métodos De Preparación
Rutas Sintéticas y Condiciones de Reacción: Indinavir se sintetiza mediante un proceso de múltiples pasos que implica la formación de varios intermediariosLas condiciones de reacción generalmente implican el uso de solventes orgánicos, catalizadores y temperaturas controladas para garantizar que las transformaciones químicas deseadas ocurran de manera eficiente .
Métodos de Producción Industrial: La producción industrial de this compound implica la síntesis a gran escala utilizando condiciones de reacción optimizadas para maximizar el rendimiento y la pureza. El proceso incluye pasos de purificación rigurosos, como la cristalización y la cromatografía, para obtener el producto final en su forma pura. La producción se lleva a cabo bajo medidas estrictas de control de calidad para garantizar la consistencia y la seguridad .
Análisis De Reacciones Químicas
Tipos de Reacciones: Indinavir experimenta diversas reacciones químicas, entre ellas:
Oxidación: this compound se puede oxidar en condiciones específicas, lo que lleva a la formación de derivados oxidados.
Reducción: Las reacciones de reducción pueden modificar los grupos funcionales dentro de this compound, lo que podría alterar su actividad.
Reactivos y Condiciones Comunes:
Oxidación: Los agentes oxidantes comunes incluyen peróxido de hidrógeno y permanganato de potasio.
Reducción: Se utilizan agentes reductores como borohidruro de sodio e hidruro de aluminio y litio.
Principales Productos Formados: Los principales productos formados a partir de estas reacciones dependen de los reactivos y las condiciones específicas utilizadas. Por ejemplo, la oxidación puede llevar a la formación de derivados hidroxilados o cetónicos, mientras que la reducción puede producir alcoholes o aminas .
Comparación Con Compuestos Similares
- 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, this compound’s molecular structure allows for distinct interactions with the enzyme’s active site, leading to different pharmacokinetic and pharmacodynamic profiles. Additionally, this compound’s solubility and bioavailability are enhanced by its specific chemical modifications .
This compound’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 .
Actividad Biológica
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 this compound, including its pharmacodynamics, clinical efficacy, side effects, and case studies that highlight its therapeutic applications.
This compound 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, this compound inhibits the formation of mature and infectious virions, thereby reducing viral load in infected individuals. The inhibitory concentration (IC50) for this compound is approximately 50-100 nM in cell culture models .
Pharmacokinetics
This compound 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 this compound
Property | Value |
---|---|
Absorption | Rapid (Tmax ~0.8 h) |
Protein Binding | ~60% |
Renal Clearance | Exceeds glomerular filtration |
IC50 | 50-100 nM |
Clinical Efficacy
This compound 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 this compound 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: this compound in Kaposi's Sarcoma Treatment
- Study Design : A phase II trial assessed this compound'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, this compound is associated with several side effects, particularly renal complications. A retrospective cohort study reported an incidence of this compound-associated renal complications (IRC) at 7.3%, with symptoms including loin pain and renal colic . The study indicated that prolonged exposure to this compound (>74 weeks) reduced the risk of IRC.
Table 2: Incidence of this compound-Associated Renal Complications
Complication Type | Incidence (%) |
---|---|
Loin Pain | 58 |
Renal Colic | 42 |
Dysuria | 19 |
Insulin Resistance
Research has shown that this compound can induce insulin resistance, leading to impaired glucose tolerance in patients. A study found that a single dose of this compound 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.
Propiedades
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 | 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 | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
InChI Key |
CBVCZFGXHXORBI-PXQQMZJSSA-N | |
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 | 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 | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C36H47N5O4 | |
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)) | |
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 | |
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 | PubChem | |
URL | https://pubchem.ncbi.nlm.nih.gov | |
Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid | |
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 | |
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. | |
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 | |
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 | |
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 |
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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
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