Daclatasvir
Overview
Description
Daclatasvir is an antiviral medication used in combination with other medications to treat hepatitis C virus (HCV) infections. It is marketed under the brand name Daklinza. This compound works by inhibiting the HCV protein NS5A, which is essential for viral replication . This compound is particularly effective against HCV genotypes 1, 3, and 4 .
Mechanism of Action
Target of Action
Daclatasvir is a direct-acting antiviral agent that primarily targets the Hepatitis C Virus (HCV) . It specifically binds to NS5A , a nonstructural phosphoprotein encoded by HCV . NS5A is part of a functional replication complex responsible for viral RNA genome amplification .
Mode of Action
This compound exerts its antiviral action by preventing RNA replication and virion assembly . It binds to the N-terminus of the D1 domain of NS5A, which prevents its interaction with host cell proteins and membranes required for virion replication complex assembly . This compound targets both the cis- and trans-acting functions of NS5A and disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status .
Biochemical Pathways
The primary biochemical pathway affected by this compound is the HCV RNA replication process . By binding to NS5A, this compound disrupts the replication of the HCV RNA genome, thereby inhibiting the assembly of new virions .
Pharmacokinetics
This compound undergoes rapid absorption, with a time to reach maximum plasma concentration of 1–2 hours and an elimination half-life of approximately 10 to 14 hours . Steady state is achieved by day 4 in multiple-ascending dose studies . This compound has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion . Renal clearance is a minor route of elimination for this compound .
Result of Action
The primary result of this compound’s action is the inhibition of HCV replication, leading to a reduction in the viral load . This can lead to significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality .
Safety and Hazards
Common side effects when used with sofusbivir and daclatasvir include headache, feeling tired, and nausea. With this compound, sofosbuvir, and ribavirin the most common side effects are headache, feeling tired, nausea, and red blood cell breakdown. It should not be used with St. John’s wort, rifampin, or carbamazepine .
Future Directions
Daclatasvir was the first drug with demonstrated safety and therapeutic efficacy in treating HCV genotype 3 without the need for co-administration of interferon or Ribavirin . It is on the World Health Organization’s List of Essential Medicines . The brand Daklinza is being withdrawn by Bristol Myers Squibb in countries where the drug is not typically prescribed, and Bristol Myers Squibb says it will not enforce its patents in those countries .
Biochemical Analysis
Biochemical Properties
Daclatasvir exerts its antiviral action by preventing RNA replication and virion assembly via binding to NS5A, a nonstructural phosphoprotein encoded by HCV . Binding to the N-terminus of the D1 domain of NS5A prevents its interaction with host cell proteins and membranes required for virion replication complex assembly .
Cellular Effects
This compound has a profound effect on viral load with onset that is more rapid than had been seen previously with either NS3 protease or NS5B polymerase inhibitors . It disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status .
Molecular Mechanism
This compound works by inhibiting the HCV protein NS5A . It targets both the cis- and trans-acting functions of NS5A and disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status .
Temporal Effects in Laboratory Settings
This compound undergoes rapid absorption, with a time to reach maximum plasma concentration of 1–2 h and an elimination half-life of 10 to 14 h observed in single-ascending dose studies . Steady state was achieved by day 4 in multiple-ascending dose studies .
Dosage Effects in Animal Models
In-vivo animal studies suggested that this compound concentrates in livers (mice, rats, dogs, and monkeys), with liver-to-serum or liver-to-plasma area under the concentration–time curve (AUC) ratios ranging from 1.9 to 17 in the different animal species tested .
Metabolic Pathways
This compound has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion . Renal clearance is a minor route of elimination for this compound .
Transport and Distribution
This compound is transported and distributed within cells and tissues via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion .
Subcellular Localization
Given its mechanism of action, it is likely to be found in close proximity to the HCV NS5A protein, which is associated with the endoplasmic reticulum membrane where the HCV replication complex is located .
Preparation Methods
Synthetic Routes and Reaction Conditions: The synthesis of daclatasvir involves multiple steps, starting from commercially available starting materials. . The reaction conditions typically involve the use of organic solvents, catalysts, and controlled temperatures to ensure high yield and purity.
Industrial Production Methods: Industrial production of this compound follows a similar synthetic route but is optimized for large-scale production. This involves the use of high-efficiency reactors, continuous flow processes, and stringent quality control measures to ensure consistency and compliance with regulatory standards .
Chemical Reactions Analysis
Types of Reactions: Daclatasvir undergoes various chemical reactions, including:
Oxidation: this compound can be oxidized under specific conditions, leading to the formation of oxidized derivatives.
Reduction: Reduction reactions can modify the imidazole rings or other functional groups within the molecule.
Substitution: Substitution reactions can occur at the biphenyl core or the imidazole rings, leading to the formation of different analogs.
Common Reagents and Conditions:
Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.
Reduction: Reducing agents such as sodium borohydride and lithium aluminum hydride are used.
Substitution: Various halogenating agents and nucleophiles are employed for substitution reactions.
Major Products Formed: The major products formed from these reactions include oxidized derivatives, reduced analogs, and substituted compounds with modified pharmacological properties .
Scientific Research Applications
Daclatasvir has a wide range of scientific research applications:
Chemistry: It serves as a model compound for studying antiviral drug design and synthesis.
Biology: this compound is used to study the mechanisms of viral replication and the role of NS5A in HCV.
Medicine: It is a crucial component of combination therapies for treating chronic HCV infections, leading to high sustained virological response rates.
Industry: this compound’s production and formulation are studied to improve manufacturing processes and drug delivery systems
Comparison with Similar Compounds
Sofosbuvir: Another antiviral medication used in combination with daclatasvir for treating HCV. It inhibits the HCV RNA polymerase NS5B.
Ledipasvir: Similar to this compound, it inhibits the NS5A protein but has different pharmacokinetic properties.
Velpatasvir: Another NS5A inhibitor with a broader spectrum of activity against various HCV genotypes.
Uniqueness of this compound: this compound is unique due to its high selectivity and potency against HCV NS5A. It has a well-characterized pharmacokinetic profile, allowing for once-daily oral administration. Additionally, this compound has shown efficacy in patients with advanced liver disease and those co-infected with HIV .
Properties
IUPAC Name |
methyl N-[(2S)-1-[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-5-yl]phenyl]phenyl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C40H50N8O6/c1-23(2)33(45-39(51)53-5)37(49)47-19-7-9-31(47)35-41-21-29(43-35)27-15-11-25(12-16-27)26-13-17-28(18-14-26)30-22-42-36(44-30)32-10-8-20-48(32)38(50)34(24(3)4)46-40(52)54-6/h11-18,21-24,31-34H,7-10,19-20H2,1-6H3,(H,41,43)(H,42,44)(H,45,51)(H,46,52)/t31-,32-,33-,34-/m0/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
FKRSSPOQAMALKA-CUPIEXAXSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC(C)C(C(=O)N1CCCC1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)C6CCCN6C(=O)C(C(C)C)NC(=O)OC)NC(=O)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
CC(C)[C@@H](C(=O)N1CCC[C@H]1C2=NC=C(N2)C3=CC=C(C=C3)C4=CC=C(C=C4)C5=CN=C(N5)[C@@H]6CCCN6C(=O)[C@H](C(C)C)NC(=O)OC)NC(=O)OC |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C40H50N8O6 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID901026404 |
Source
|
| Record name | Daclatasvir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID901026404 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
738.9 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Solubility |
Freely soluble (>700 mg/mL) |
Source
|
| Record name | Daclatasvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09102 | |
| 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) | |
Mechanism of Action |
NS5A is a viral nonstructural phospoprotein that is part of a functional replication complex in charge of viral RNA genome amplification on endoplasmic reticulum membranes. It has the ability to bind to HCV RNA. It is shown to have two distinct functions in HCV RNA replication based on phosphorylated states. Maintaining the HCV replication complex is mediated by the cis-acting function of basally phosphorylated NS5A and the trans-acting function of hyperphosphorylated NS5A modulates HCV assembly and infectious particle formation. Daclatasvir is shown to disrupt hyperphosphorylated NS5A proteins thus interfere with the function of new HCV replication complexes. It is also reported that daclatasvir also blocks both intracellular viral RNA synthesis and virion assembly/secretion in vivo. |
Source
|
| Record name | Daclatasvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09102 | |
| 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. |
1009119-64-5 |
Source
|
| Record name | Daclatasvir | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=1009119-64-5 | |
| 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 | Daclatasvir | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09102 | |
| 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 | Daclatasvir | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID901026404 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Daclatasvir | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | DACLATASVIR | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/LI2427F9CI | |
| 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. | |
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
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
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