Grazoprevir (MK5172)
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MedKoo CAT#: 501205

CAS#: 1350514-68-9 (free)

Description: Grazoprevir, also known as MK5172, is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, following promising results in Phase II when used in combination with the NS5A replication complex inhibitor elbasvir, either with or without ribavirin.Grazoprevir is a second generation hepatitis C virus protease inhibitor acting at the NS3/4a protease targets. It has good activity against a range of HCV genotype variants, including some that are resistant to most currently used antiviral medications.


Chemical Structure

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Grazoprevir (MK5172)
CAS# 1350514-68-9 (free)

Theoretical Analysis

MedKoo Cat#: 501205
Name: Grazoprevir (MK5172)
CAS#: 1350514-68-9 (free)
Chemical Formula: C38H50N6O9S
Exact Mass: 766.336
Molecular Weight: 766.911
Elemental Analysis: C, 59.51; H, 6.57; N, 10.96; O, 18.78; S, 4.18

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1.0g USD 2850.0 Same day
2.0g USD 3650.0 Same day
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Related CAS #: 1350514-68-9 (free)   1350462-55-3 (hydrate)   1206524-86-8 (potassium)   1425038-27-2 (sodium)    

Synonym: MK-5172; MK 5172; MK5172; Grazoprevir. trade name: Zepatier‎.

IUPAC/Chemical Name: (33R,35S,91R,92R,5S)-5-(tert-butyl)-N-((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalina-3(3,1)-pyrrolidina-9(1,2)-cyclopropanacyclotetradecaphane-35-carboxamide

InChi Key: OBMNJSNZOWALQB-NCQNOWPTSA-N

InChi Code: InChI=1S/C38H50N6O9S/c1-6-22-19-38(22,35(47)43-54(49,50)25-13-14-25)42-32(45)29-18-24-20-44(29)34(46)31(37(2,3)4)41-36(48)53-30-16-21(30)10-8-7-9-11-27-33(52-24)40-28-17-23(51-5)12-15-26(28)39-27/h6,12,15,17,21-22,24-25,29-31H,1,7-11,13-14,16,18-20H2,2-5H3,(H,41,48)(H,42,45)(H,43,47)/t21-,22-,24-,29+,30-,31-,38-/m1/s1

SMILES Code: O=C([C@H]1N2C([C@H](C(C)(C)C)NC(O[C@]3([H])C[C@@]3([H])CCCCCC4=NC5=CC=C(OC)C=C5N=C4O[C@](C2)([H])C1)=O)=O)N[C@@]6(C(NS(=O)(C7CC7)=O)=O)[C@H](C=C)C6

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >5 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Grazoprevir (MK-5172) is a selective inhibitor of Hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants, with Kis of 0.01 nM (gt1b), 0.01 nM (gt1a), 0.08 nM (gt2a), 0.15 nM (gt2b), 0.90 nM (gt3a), respectively.
In vitro activity: Unlike all other HCV PIs with known cocrystal structures, MK-5172 interacts with the catalytic triad in a unique conformation where the P2 quinoxaline moiety packs largely against the catalytic residues H57 and D81 (Figure 1). The P1–P4 peptidomimetic inhibitor scaffold spans the S1–S4 binding pockets interacting with the carbonyl oxygens of R155 and A157 as well as the Nε of A157. The P1′ acylsulfonamide is positioned in the oxyanion hole and hydrogen bonds to H57, G137, and S139. This binding mode is unchanged when the P2–P4 macrocycle is removed (5172-linear) or replaced with a P1–P3 macrocycle (5172-mcP1P3). Therefore, the binding mode of MK-5172 is a function of the P2 moiety rather than the macrocycle. Reference: ACS Chem Biol. 2016 Apr 15; 11(4): 900–909. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099976/
In vivo activity: To demonstrate in vivo efficacy, MK-5172 was administered orally to three chronically HCV-infected chimpanzees at a dose of 1 mg per kg twice daily for 7 days. Two of the chimpanzees had wild-type (WT) gt1a or gt1b infections with high viral titers (∼106 IU/ml). A third chimpanzee had a modest viral titer (∼104 IU/ml) that was gt1a NS3 R155K virus. This chimpanzee maintained a chronic R155K viral infection in the absence of prior experimental treatment with an HCV small molecule inhibitor (J. Fontenot, personal communication). Pharmacodynamic responses to MK-5172 are shown in Fig. 4A. Reference: Antimicrob Agents Chemother. 2012 Aug; 56(8): 4161–4167. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421554/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 58.33 76.06
DMF 30.0 39.12
DMF:PBS (pH 7.2) (1:4) 0.2 0.26
Ethanol 57.5 74.98

Preparing Stock Solutions

The following data is based on the product molecular weight 766.911 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Soumana DI, Kurt Yilmaz N, Prachanronarong KL, Aydin C, Ali A, Schiffer CA. Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172. ACS Chem Biol. 2016 Apr 15;11(4):900-9. doi: 10.1021/acschembio.5b00647. Epub 2016 Jan 6. PMID: 26682473; PMCID: PMC5099976. 2. Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, Coleman PJ, Dimuzio JM, Ferrara M, Di Filippo M, Gates AT, Graham DJ, Harper S, Hazuda DJ, Huang Q, McHale C, Monteagudo E, Pucci V, Rowley M, Rudd MT, Soriano A, Stahlhut MW, Vacca JP, Olsen DB, Liverton NJ, Carroll SS. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7. doi: 10.1128/AAC.00324-12. Epub 2012 May 21. Erratum in: Antimicrob Agents Chemother. 2014 Aug;58(8):4995. Huang, Qian [added]. PMID: 22615282; PMCID: PMC3421554.
In vitro protocol: 1. Soumana DI, Kurt Yilmaz N, Prachanronarong KL, Aydin C, Ali A, Schiffer CA. Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172. ACS Chem Biol. 2016 Apr 15;11(4):900-9. doi: 10.1021/acschembio.5b00647. Epub 2016 Jan 6. PMID: 26682473; PMCID: PMC5099976.
In vivo protocol: 1. Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, Coleman PJ, Dimuzio JM, Ferrara M, Di Filippo M, Gates AT, Graham DJ, Harper S, Hazuda DJ, Huang Q, McHale C, Monteagudo E, Pucci V, Rowley M, Rudd MT, Soriano A, Stahlhut MW, Vacca JP, Olsen DB, Liverton NJ, Carroll SS. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012 Aug;56(8):4161-7. doi: 10.1128/AAC.00324-12. Epub 2012 May 21. Erratum in: Antimicrob Agents Chemother. 2014 Aug;58(8):4995. Huang, Qian [added]. PMID: 22615282; PMCID: PMC3421554.

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1: Hézode C, Kwo P, Sperl J, Hwang P, Long J, Talwani R, Robertson MN, Haber BA. Elbasvir/grazoprevir in women with hepatitis C virus infection taking oral contraceptives or hormone replacement therapy. Int J Womens Health. 2019 Nov 20;11:617-628. doi: 10.2147/IJWH.S203022. eCollection 2019. PubMed PMID: 31819666; PubMed Central PMCID: PMC6875497.

2: Asselah T, Pol S, Hezode C, Loustaud-Ratti V, Leroy V, Ahmed SNS, Ozenne V, Bronowicki JP, Larrey D, Tran A, Alric L, Nguyen-Khac E, Robertson MN, Hanna GJ, Brown D, Asante-Appiah E, Su FH, Hwang P, Hall JD, Guidoum A, Hagen K, Haber BA, Talwani R, Serfaty L. Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus: genotype 4 infection: a randomized study. Liver Int. 2019 Nov 25. doi: 10.1111/liv.14313. [Epub ahead of print] PubMed PMID: 31765046.

3: Zarębska-Michaluk D, Jaroszewicz J, Buczyńska I, Simon K, Lorenc B, Tudrujek-Zdunek M, Tomasiewicz K, Sitko M, Garlicki A, Janczewska E, Dybowska D, Halota W, Pawłowska M, Pabjan P, Mazur W, Czauż-Andrzejuk A, Berak H, Horban A, Socha Ł, Klapaczyński J, Piekarska A, Blaszkowska M, Belica-Wdowik T, Dobracka B, Tronina O, Deroń Z, Białkowska-Warzecha J, Laurans Ł, Flisiak R. Real world experience with Grazoprevir/Elbasvir in the treatment of previously "difficult to treat" patients infected with HCV genotype 1 and 4. J Gastroenterol Hepatol. 2019 Nov 16. doi: 10.1111/jgh.14936. [Epub ahead of print] PubMed PMID: 31734959.

4: Chen L, Chen J, Lu M, Stämpfli A. Simultaneous determination of elbasvir and grazoprevir in fixed-dose combination and mass spectral characterization of each degradation product by UHPLC-ESI-QTOF-MS/MS. J Pharm Biomed Anal. 2019 Nov 3:112964. doi: 10.1016/j.jpba.2019.112964. [Epub ahead of print] PubMed PMID: 31711865.

5: Tsai TC, Deng ST, Hsu CW. The efficacy and safety of elbasvir/grazoprevir treatment in HCV genotype 1 patients in Taiwan. J Med Virol. 2020 Feb;92(2):219-226. doi: 10.1002/jmv.25605. Epub 2019 Oct 22. PubMed PMID: 31599455.

6: Liu CJ, Tseng KC, Lo CC, Tseng IH, Cheng PN. Limited drug-drug interaction of elbasvir/grazoprevir for chronic hepatitis C. J Formos Med Assoc. 2019 Oct 5. pii: S0929-6646(19)30666-7. doi: 10.1016/j.jfma.2019.09.011. [Epub ahead of print] PubMed PMID: 31594667.

7: DeCarolis DD, Chen YC, Westanmo AD, Conley C, Gravely AA, Khan FB. Decreased warfarin sensitivity among patients treated with elbasvir and grazoprevir for hepatitis C infection. Am J Health Syst Pharm. 2019 Sep 1;76(17):1273-1280. doi: 10.1093/ajhp/zxz127. PubMed PMID: 31418789.

8: Papaluca T, Sinclair M, Gow P, Pianko S, Sievert W, Arachchi N, Cameron K, Bowden S, O'Keefe J, Doyle J, Stoove M, Hellard M, Iser D, Thompson A. Retreatment with elbasvir, grazoprevir, sofosbuvir ± ribavirin is effective for GT3 and GT1/4/6 HCV infection after relapse. Liver Int. 2019 Dec;39(12):2285-2290. doi: 10.1111/liv.14201. Epub 2019 Aug 13. PubMed PMID: 31355968.

9: Guo Z, Caro L, Robertson MN, Hwang P, Hoover P, Wudarski C, Maiuri K, Wang YH, Mogg R, Mehrotra DV, Blanchard R, Shaw PM. The pharmacogenetics of OATP1B1 variants and their impact on the pharmacokinetics and efficacy of elbasvir/grazoprevir. Pharmacogenomics. 2019 Jun;20(9):631-641. doi: 10.2217/pgs-2019-0022. PubMed PMID: 31250727.

10: Feng HP, Guo Z, Caro L, Talaty JE, Mangin E, Panebianco D, Fandozzi C, Zhu Y, Marshall W, Huang X, Hanley WD, Jumes P, Valesky R, Martinho M, Butterton JR, Iwamoto M, Yeh WW. Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate. Clin Pharmacol Drug Dev. 2019 Oct;8(7):962-970. doi: 10.1002/cpdd.701. Epub 2019 Jun 7. PubMed PMID: 31173674.

11: Feng HP, Guo Z, Fandozzi C, Panebianco D, Caro L, Wolford D, Dreyer DP, Valesky R, Martinho M, Rizk ML, Iwamoto M, Yeh WW. Pharmacokinetic Interactions Between the Fixed-Dose Combinations of Elvitegravir/Cobicistat/Tenofovir Disoproxil Fumarate/Emtricitabine and Elbasvir/Grazoprevir in Healthy Adult Participants. Clin Pharmacol Drug Dev. 2019 Oct;8(7):952-961. doi: 10.1002/cpdd.702. Epub 2019 Jun 7. PubMed PMID: 31173673.

12: Lee YJ, Heo J, Kim DY, Chung WJ, Tak WY, Kim YJ, Paik SW, Sim E, Kulasingam S, Talwani R, Haber B, Hwang P. An integrated analysis of elbasvir/grazoprevir in Korean patients with hepatitis C virus genotype 1b infection. Clin Mol Hepatol. 2019 May 28. doi: 10.3350/cmh.2019.0006. [Epub ahead of print] PubMed PMID: 31132846.

13: Lin YC, Li SW, Ku SY, Hsieh HT, Lin MH, Chang SY, Wu WW, Sun NL, Cheng SH, Cheng CY. Grazoprevir/elbasvir in peginterferon alfa plus ribavirin experienced patients with chronic genotype 1 HCV/HIV co-infection: a non-randomized, open-label clinical trial. Infect Drug Resist. 2019 Apr 18;12:937-945. doi: 10.2147/IDR.S206938. eCollection 2019. PubMed PMID: 31114268; PubMed Central PMCID: PMC6489556.

14: Mashiba T, Joko K, Kurosaki M, Ochi H, Hasebe C, Akahane T, Sohda T, Tsuji K, Mitsuda A, Kimura H, Narita R, Ogawa C, Furuta K, Shigeno M, Okushin H, Ito H, Kusakabe A, Satou T, Kawanami C, Nakata R, Kobashi H, Tamada T, Ide Y, Yagisawa H, Morita A, Matsushita T, Okada K, Izumi N. Real-world efficacy of elbasvir and grazoprevir for hepatitis C virus (genotype 1): A nationwide, multicenter study by the Japanese Red Cross Hospital Liver Study Group. Hepatol Res. 2019 Oct;49(10):1114-1120. doi: 10.1111/hepr.13362. Epub 2019 Jun 14. PubMed PMID: 31077527.

15: Huang CF, Hung CH, Cheng PN, Bair MJ, Huang YH, Kao JH, Hsu SJ, Lee PL, Chen JJ, Chien RN, Peng CY, Lin CY, Hsieh TY, Cheng CH, Dai CY, Huang JF, Chuang WL, Yu ML. An Open-Label, Randomized, Active-Controlled Trial of 8 Versus 12 Weeks of Elbasvir/Grazoprevir for Treatment-Naive Patients With Chronic Hepatitis C Genotype 1b Infection and Mild Fibrosis (EGALITE Study): Impact of Baseline Viral Loads and NS5A Resistance-Associated Substitutions. J Infect Dis. 2019 Jul 19;220(4):557-566. doi: 10.1093/infdis/jiz154. PubMed PMID: 30957170.

16: Jacobson IM, Poordad F, Firpi-Morell R, Everson GT, Verna EC, Bhanja S, Hwang P, Caro L, Robertson M, Charles ED, Platt H. Elbasvir/Grazoprevir in People With Hepatitis C Genotype 1 Infection and Child-Pugh Class B Cirrhosis: The C-SALT Study. Clin Transl Gastroenterol. 2019 Apr;10(4):e00007. doi: 10.14309/ctg.0000000000000007. PubMed PMID: 30939489; PubMed Central PMCID: PMC6493687.

17: Flamm S, Peng CY, Shibolet O, Nahass R, Hwang P, Barr E, Robertson MN, Haber BA. Efficacy and Safety of Elbasvir/Grazoprevir in Hepatitis C Virus GT1- and GT4-Infected People Aged 65 Years or Older. Gerontol Geriatr Med. 2019 Jan 22;5:2333721418817398. doi: 10.1177/2333721418817398. eCollection 2019 Jan-Dec. PubMed PMID: 30891470; PubMed Central PMCID: PMC6415929.

18: Ankrom W, Sanchez RI, Yee KL, Fan L, Mitra P, Wolford D, Triantafyllou I, Sterling LM, Stoch SA, Iwamoto M, Khalilieh S. Investigation of Pharmacokinetic Interactions between Doravirine and Elbasvir-Grazoprevir and Ledipasvir-Sofosbuvir. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: e02491-18. doi: 10.1128/AAC.02491-18. Print 2019 May. PubMed PMID: 30782982; PubMed Central PMCID: PMC6496042.

19: Wei L, Kumada H, Perumalswami PV, Tanwandee T, Cheng W, Heo J, Cheng PN, Hwang P, Mu SM, Zhao XM, Asante-Appiah E, Caro L, Hanna GJ, Robertson MN, Haber BA, Talwani R. Safety and efficacy of elbasvir/grazoprevir in Asian participants with hepatitis C virus genotypes 1 and 4 infection. J Gastroenterol Hepatol. 2019 Sep;34(9):1597-1603. doi: 10.1111/jgh.14636. Epub 2019 Apr 17. PubMed PMID: 30779220.

20: van Seyen M, de Graaff Teulen MJA, van Erp NP, Burger DM. Quantification of second generation direct-acting antivirals daclatasvir, elbasvir, grazoprevir, ledipasvir, simeprevir, sofosbuvir and velpatasvir in human plasma by UPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Mar 15;1110-1111:15-24. doi: 10.1016/j.jchromb.2019.01.024. Epub 2019 Jan 28. PubMed PMID: 30776611.



Additional Information

MK-5172, is a Next Generation HCV NS3/4a Protease Inhibitor with a Broad HCV Genotypic Activity Spectrum and Potent Activity Against Known Resistance Mutants, in Genotype 1 and 3 HCV-Infected Patients. MK-5172 exhibits excellent selectivity over other serine proteases such as elastase and trypsin (no measurable inhibition), and shows only modest inhibitory potency with chymotrypsin (IC50 = 1.5 µM; 75,000-fold selective). In the genotype 1b replicon assay, MK-5172 potently inhibits viral replication (IC50 = 2 nM) and demonstrates a modest shift in the presence of 50% NHS (EC50 = 9.5 nM). In vitro, MK-5172 inhibits the NS3/4A enzyme from genotypes 1b, 2a, 2b, and 3a with Ki values of <0.02, 0.15, 0.02, and 0.7 nM, respectively. The genotype 2a replicon is also potently inhibited by MK 5172 (EC50 = 5 nM).

Other CAS# related to Grazoprevir
Grazoprevir: CAS#1350514-68-9
Grazoprevir potassium :CAS#1206524-86-8
Grazoprevir sodium: CAS#1425038-27-2
Grazoprevir hydrate: CAS#1350462-55-3