grazoprevir

grazoprevir
IUPAC name	(1aR,5S,8S,10R,22aR)-N-[(1R,2S)-1-[(Cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl]-14-methoxy-5-(2-methylpropan-2-yl)-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxamide
Width	200
CAS number	1350514-68-9
DrugBank	DB11594
UNII	1H4L27C2H2
Synonyms	MK-5172

grazoprevir is a direct-acting antiviral medication used for the treatment of chronic infection caused by the hepatitis C virus. It is a second-generation NS3/4A protease inhibitor developed by the pharmaceutical company Merck & Co. and is a key component of the fixed-dose combination drug elbasvir/grazoprevir, marketed under the brand name Zepatier. This combination therapy is indicated for patients infected with hepatitis C virus genotypes 1 and 4, representing a significant advancement in the era of interferon-free regimens.

Medical uses

Grazoprevir is co-formulated with elbasvir as a once-daily, oral tablet for the treatment of adults with chronic hepatitis C virus genotype 1 or 4 infection. The combination was approved by the Food and Drug Administration in 2016 and by the European Medicines Agency following positive results from the pivotal C-EDGE clinical trial program. Treatment regimens typically last 12 to 16 weeks and are recommended by guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. It is also used in certain patients with human immunodeficiency virus co-infection and in those with advanced chronic kidney disease, including those on hemodialysis.

Adverse effects

The fixed-dose combination of elbasvir/grazoprevir is generally well-tolerated. The most commonly reported adverse reactions in clinical trials included fatigue, headache, and nausea. Serious adverse events were infrequent but could include elevations in alanine aminotransferase levels, necessitating monitoring as per FDA labeling. As with other NS3/4A protease inhibitors, there is a potential for drug-drug interactions, particularly with strong inducers of the cytochrome P450 system, such as carbamazepine and St. John's wort.

Pharmacology

Grazoprevir exerts its antiviral effect by inhibiting the NS3/4A protease, an enzyme essential for viral replication in the hepatitis C virus. This inhibition prevents the cleavage of the hepatitis C virus polyprotein into mature functional proteins, thereby halting the production of new infectious virions. Pharmacokinetic studies show grazoprevir is metabolized primarily via the cytochrome P450 3A4 pathway and is a substrate for the drug transporters P-glycoprotein and OATP1B1/3. Its pharmacokinetic profile supports once-daily dosing and it achieves high concentrations in the liver.

Chemistry

Grazoprevir is a macrocyclic inhibitor of the hepatitis C virus NS3/4A protease. Its complex structure features a fused ring system designed to fit precisely into the enzyme's active site, providing potent activity against a broad range of hepatitis C virus genotypes and known resistance-associated variants. The synthesis of grazoprevir, developed by researchers at Merck & Co., involves multiple stereoselective steps to construct its challenging quinoxaline-containing macrocycle. The compound is a white to off-white crystalline powder with low solubility.

History

The discovery and development of grazoprevir originated from research programs at Merck & Co. following the introduction of first-generation protease inhibitors like boceprevir and telaprevir. It was designed to overcome limitations of earlier agents, including improved potency against hepatitis C virus genotype 1a and a higher barrier to resistance. The drug's clinical development accelerated after the acquisition of Idenix Pharmaceuticals by Merck & Co.. Pivotal phase III trials, including C-EDGE and C-SURFER, demonstrated high sustained virologic response rates, leading to its regulatory approvals in 2016.

Society and culture

The approval of the elbasvir/grazoprevir combination was a significant event in the global effort to eliminate hepatitis C virus, as endorsed by the World Health Organization. Its introduction increased therapeutic options and competition in the marketplace, which included other regimens from Gilead Sciences and AbbVie. Access and pricing have been subjects of debate within healthcare systems like the National Health Service in the United Kingdom. The drug is listed on the World Health Organization Model List of Essential Medicines, highlighting its public health importance.

Category:Antiviral drugs Category:Hepatitis C Category:Merck & Co.