Ledipasvir

ChEBI: A benzimidazole derivative that is used in combination with sofosbuvir (under the trade name Harvoni) for the treatment of chronic hepatitis C genotype 1 infection.

Ledipasvir is a benzimidazole derivative that is used in combination with sofosbuvir (under the trade name Harvoni) for the treatment of chronic hepatitis C genotype 1 infection. It has a role as an antiviral drug and a hepatitis C protease inhibitor. It is a carbamate ester, a L-valine derivative, a bridged compound, a carboxamide, a benzimidazole, a member of fluorenes, an organofluorine compound, a member of imidazoles, a N-acylpyrrolidine and an azaspiro compound.|Ledipasvir is a direct acting antiviral (DAA) medication used as part of combination therapy to treat chronic Hepatitis C, an infectious liver disease caused by infection with Hepatitis C Virus (HCV). HCV is a single-stranded RNA virus that is categorized into nine distinct genotypes, with genotype 1 being the most common in the United States, and affecting 72% of all chronic HCV patients. Treatment options for chronic Hepatitis C have advanced significantly since 2011, with the development of Direct Acting Antivirals (DAAs) such as ledipasvir. More specifically, ledipasvir is an inhibitor of the Hepatitis C Virus (HCV) Non-Structural Protein 5A (NS5A), which is required for viral RNA replication and assembly of HCV virions. Although its exact mechanism of action is unknown, it is postulated to prevent hyperphosphorylation of NS5A which is required for viral protein production. It is effective against genotypes 1a, 1b, 4a, and 5a and with a lesser activity against genotypes 2a and 3a of HCV. Ledipasvir and other direct acting antivirals are very potent options for the treatment of Hepatitis C, as they exhibit a high barrier to the development of resistance. This is an important advantage relative to HCV drugs that target other viral enzymes such as the protease, for which rapid development of resistance has proven to be an important cause of therapeutic failure. In a joint recommendation published in 2016, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommend ledipasvir as a first line therapy option in combination with [sofosbuvir] for the treatment of HCV genotypes 1a, 1b, 4, 5, and 6. Treatment with ledipasvir is used with the intent to cure, or achieve a sustained virologic response (SVR), after 12 weeks of daily therapy. SVR and eradication of HCV infection is associated with significant long-term health benefits including reduced liver-related damage, improved quality of life, reduced incidence of Hepatocellular Carcinoma, and reduced all-cause mortality. Treatment with direct acting antivirals such as ledipasvir is associated with very minimal side effects, with the most common being headache and fatigue. Lack of significant side effects and short duration of therapy is a considerable advantage over older interferon- and ribavirin-based regimens, which were limited by infusion site reactions, reduced blood count, and neuropsychiatric effects. Since 2014, ledipasvir has been available as a fixed dose combination product with [sofosbuvir] (tradename Harvoni) used for the treatment of chronic Hepatitis C. Approved in October 2014 by the FDA, Harvoni is indicated for the treatment of HCV genotypes 1, 4, 5, and 6 with or without [ribavirin] depending on the level of liver damage or cirrhosis. When combined together, ledipasvir and sofosbuvir as the combination product Harvoni has been shown to achieve a SVR between 93 and 99% after 12 weeks of treatment. Its use has also proven successful in the treatment of HCV in patients co-infected with HIV.|Ledipasvir is a Hepatitis C Virus NS5A Inhibitor. The mechanism of action of ledipasvir is as a P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor.|Ledipasvir is an orally available inhibitor of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) replication complex, with potential activity against HCV. Upon oral administration and after intracellular uptake, ledipasvir binds to and blocks the activity of the NS5A protein. This results in the disruption of the viral RNA replication complex, blockage of HCV RNA production, and inhibition of viral replication. NS5A, a zinc-binding and proline-rich hydrophilic phosphoprotein, plays a crucial role in HCV RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family; HCV infection is associated with the development of hepatocellular carcinoma (HCC).

Preparation steps: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-hydroxybenzotriazole, N-(methoxycarbonyl)-L-proline and N, N-dimethylformamide were added to the reaction kettle, the reaction mixture was stirred at 20 C for 0.5 hours, and the solution was then cooled to 0 C. LD-P and N-methylmorpholine were added to the reactor, naturally warmed to room temperature, and stirring was continued for 3.5 hours. Ethyl acetate and water were added, the layers were separated, and the organic phase was washed with 4% sodium hydrogen carbonate and water, and then The organic layer was distilled to 2 volumes, cooled to 20 C, acetone was added to the reactor, stirring was continued for 2.5 hours, and the mixture was centrifuged. The filter cake was washed with acetone and dried to obtain a solid LD-Q.Compound 1?-LDV-Bz-Bz (5.25 g, 4.5 mmol), potassium phosphate aqueous solution (1M/L, 50 mL) and tert-amyl alcohol (50 mL) were added to a three-necked flask, and the temperature was raised to 90 C. The mixture was stirred for 5 hours, then cooled to room temperature and extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give the product (4 g, yield 100%).To a three-necked flask compound 1?-LDV-Boc-Boc (5.45 g, 5 mmol) and DCM (40 mL) were added, to which a solution of HCl in dioxane (4 M/L, 40 mL) was added dropwise with stirring at 10 C. After the addition the mixture was stirred for 5 hours. Then the solvent was distilled off to give the product (4.44 g, yield 100%).Compound 9 hydrochloride (4.2 g, 5 mmol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (0.963 g, 5.5 mmol), EDCI (1.437 g, 7.5 mmol), HOBt (1.013 g, 7.5 mmol), triethylamine (2.53 g, 25 mmol) and DMF (100 mL) were added into a three-necked bottle. The mixture was stirred at 20 C. for 16 hours. After that ethyl acetate (100 mL) was added and the mixture was washed with brine (200 mL) twice. The organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off to give the product (4.0 g, yield 90%) in which the content of compound 1-LDV is 99% and the content of defluorinated impurity is 0.15% (220 nm).Compound 13-Br (3.4 g, 5.675 mmol), compound 14-B (3.1 g, 6.243 mmol), PdCl2(dppf) (0.141 g, 0.2838 mmol), potassium carbonate (2.353 g, 17.025 mmol), water (10 mL) and tert-amyl alcohol (50 mL) were added into a three-necked bottle. Under nitrogen the mixture was heated to 90 C. and stirred for 16 hours. After that the mixture was cooled to room temperature and ethyl acetate (100 mL) was added. The mixture was washed with brine (200 mL) twice. The organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off to give the product (4.54 g, yield 90%), in which the content of compound 1-LDV is 99.3% and the content of defluorinated impurity is 0.13% (220 nm).

Molecular Weight:889.0
XLogP3:7.4
Hydrogen Bond Donor Count:4
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:12
Exact Mass:888.41343780
Monoisotopic Mass:888.41343780
Topological Polar Surface Area:175
Heavy Atom Count:65
Complexity:1820
Defined Atom Stereocenter Count:6
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes