MK-5172 (Synonyms: MK-5172)

Inhibitory assays

Inhibition of HCV NS3/4A protease activity in reaction mixtures containing MK-5172, vaniprevir, or the reference compounds danoprevir and TMC435 was determined in a time-resolved fluorescence assay. Cell-based HCV replicon assays were conducted in genotype 1b (con1) stable cell line HB1 (26) or a gt2a cell line (JFH) in the presence of either 10% fetal bovine serum (FBS) or 40% normal human serum (NHS). For in vitro resistance selections, 100,000 HB1 cells were seeded into a T162 Z-top flask and cultured in the presence of 0.5 mg/ml G418 and the desired concentration of MK-5172. Cells were cultured for approximately 3 weeks with regular exchanges of medium until sufficient cell death had occurred to enable distinct colonies to form. After expansion, total RNA was isolated, used as a template to generate NS3/4a cDNA, and sequenced using conventional molecular biology techniques.

Cell lines

A genotype/mutant panel of stable replicon cell lines

Preparation method

The solubility of this compound in DMSO is >38.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

2-10 nM, 3 weeks

Applications

MK-5172 demonstrated subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a. MK-5172 was efficacious across the genetically diverse range of genotype 1 infections encountered in clinical settings with EC50s ranged narrowly between 0.3 and 5.9 nM. In Genotype 1b replicon cells, pre- treatment with MK-5172 resulted in little apparent cell growth and limited recovery of replicon RNA levels.

Animal models

Chimpanzees, Dogs, Rats

Dosage form

Oral administration, 1 mg/kg, twice daily for 7 days

Application

MK-5172 demonstrated low to moderate clearance and a modest half-life in both rat and dog. Oral administration of MK-5172 (1 mg/kg) demonstrated modest bioavailability of 12 to 13%, with moderate plasma exposure in both species. The 24-h trough liver concentrations were 0.2 μM in rat and 1.4 μM in dog (1 mg/kg), yielding exposure multiples of 27- to 200-fold over the serum-adjusted replicon EC50. In chronic-HCV-infected chimpanzees harboring gt1a, gt1b, or gt1a NS3 R155K infections, treatment with MK-5172 (1 mg/kg, b.i.d.) demonstrated efficacy in vivo.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Summa, V., Ludmerer, S. W., McCauley, J. A., Fandozzi, C., Burlein, C., Claudio, G., ... & Gates, A. T. (2012). MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrobial agents and chemotherapy, AAC-00324.