Discovery of potent macrocyclic HCV NS5A inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 26, Issue 15, 2016, Pages 3793-3799

  Yu, Wensheng ^a   Vibulbhan, Bancha ^a   Rosenblum, Stuart B ^a   Martin, Gregory S ^b   Vellekoop, A Samuel ^b   Holst, Christian L ^b   Coburn, Craig A ^a   Wong, Michael ^a   Selyutin, Oleg ^a   Ji, Tao ^c   Zhong, Bin ^c   Hu, Bin ^c   Chen, Lei ^a   Dwyer, Michael P ^a   Jiang, Yueheng ^a   Nair, Anilkumar G ^a   Tong, Ling ^a   Zeng, Qingbei ^a   Agrawal, Sony ^a   Carr, Donna ^a   Rokosz, Laura ^a   Liu, Rong ^a   Curry, Stephanie ^a   McMonagle, Patricia ^a   Ingravallo, Paul ^a   Lahser, Fred ^a   Asante Appiah, Ernest ^a   Fells, James ^a   Kozlowski, Joseph A ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b ALBANY MOLECULAR RESEARCH INC   (United States)

^c WUXI APPTEC   (China)

Author keywords

DAA; HCV infection; HCV NS5A inhibitor; Macrocycle; MK 4882; MK 8325

Indexed keywords

ANTIVIRUS AGENT; MACROCYCLIC COMPOUND; MK 4882; MK 8325; NONSTRUCTURAL PROTEIN 5A INHIBITOR; UNCLASSIFIED DRUG; FUSED HETEROCYCLIC RINGS; MK-4882; MK-8325; NS-5 PROTEIN, HEPATITIS C VIRUS; VIRAL PROTEIN;

ANTIVIRAL ACTIVITY; ARTICLE; CYCLIZATION; DRUG POTENCY; DRUG SYNTHESIS; HEPATITIS C VIRUS GENOTYPE 1; HEPATITIS C VIRUS GENOTYPE 2; HEPATITIS C VIRUS GENOTYPE 3; IN VITRO STUDY; NONHUMAN; STRUCTURE ACTIVITY RELATION; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG EFFECTS; HEPACIVIRUS; HEPATITIS C; MICROBIAL SENSITIVITY TEST; SYNTHESIS; VIRUS REPLICATION;

ANTIVIRAL AGENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; HEPACIVIRUS; HEPATITIS C; HETEROCYCLIC COMPOUNDS, 4 OR MORE RINGS; MACROCYCLIC COMPOUNDS; MICROBIAL SENSITIVITY TESTS; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84973131500     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2016.05.042     Document Type: Article

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22. 20 Alignment was performed using Rapid Overlay of Chemical Structures (ROCS v. 3.2.0.4) software. A single low-energy conformation of compound 1 was used as the query molecule to align the compounds. Omega software v. 2.5.1.4 (OpenEye Scientific Software, Inc., Santa Fe, NM, USA) was used to generate up to 500 conformations of each compound using default parameters. ROCS was then employed to superimpose compound 1 and other compounds. Results were visualized using PYMOL (v. 1.7).
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25. 22 Compounds in Table 2 were prepared by using the chemistry outlined in Scheme 1 starting from different L-valine derivatives.
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27. 24 Compounds in Table 3 were prepared by using the chemistry outlined in Scheme 1.