SAR studies on a novel series of human cytomegalovirus primase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 8, 2007, Pages 2188-2192

  Chen, X ^a   Adrian, J ^a   Cushing, T ^a   DiMaio, H ^a   Liang, L ^a   Mayorga, V ^a   Miao, S ^a   Peterson, M G ^a   Powers, J P ^a   Spector, F ^a   Stein, C ^a   Wright, M ^a   Xu, D ^a   Ye, Q ^a   Jaen, J ^a  

^a AMGEN INC   (United States)

Author keywords

Anti viral; Cytomegalovirus; hCMV; Inhibitor; Primase

Indexed keywords

ANTIVIRUS AGENT; CIDOFOVIR; DNA PRIMASE; GANCICLOVIR; PYRIMIDINE DERIVATIVE; VIRUS DNA;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY TEST; DNA REPLICATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG POTENCY; DRUG SYNTHESIS; HUMAN CYTOMEGALOVIRUS; IC 50; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION;

ADMINISTRATION, ORAL; ANIMALS; ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; CYTOMEGALOVIRUS; DNA PRIMASE; DNA REPLICATION; DRUG TOXICITY; HUMANS; INHIBITORY CONCENTRATION 50; PYRIMIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL LOAD;

CYTOMEGALOVIRUS; HUMAN HERPESVIRUS 5;

EID: 33947587856     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.01.109     Document Type: Article

References (18)

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7. The luciferase screen involved infection of human foreskin fibroblasts (HFF) with a recombinant virus (rCMVLUC) containing a luciferase reporter gene under the control of HCMV UL99 promoter, inserted in the CMV genome between US9 and US10. Luciferase activity was measured following incubation with various concentrations of the drugs.
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9. 50 values represent the drug concentration required to inhibit 50% of the amount of radioactivity captured by the membrane when the infected cells were treated only with drug vehicle.
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13. The starting amine was synthesized by azide replacement of the corresponding alcohol synthesized by the method described in reference (Amouroux, R.; Slassi, A.; Saluzzo, C. Heterocycles, 1993, 36(9) 196), followed by hydrogenation.
14. The starting amine was prepared similarly to examples in Ref. 12 starting with the same alcohol followed by Mitsunobu reaction with p-chlorobenzoic acid and followed by hydrolysis, azide replacement, and reduction.
15. The starting amine was prepared by methyl Grignard reagent opening of epoxide catalyzed by CuI, azide replacement of the alcohol, and azide reduction. The enantiomerically pure amine was prepared by chiral resolution with d- or l-malic acid recrystallized in ether. The absolute stereo chemistry was determined by X-ray crystallography of the crystal of 4-iodo-N-((3R, 4S)-4-methyl-tetrahydrofuran-3-yl)benzeneulfonamide and 4-iodo-N-((3S, 4R)-4-methyl-tetrahydrofuran-3-yl)benzeneulfonamide.
16. 50 value represents the concentration of compound that inhibits cell growth by 50%.
17. 50) was calculated.
18. The viral yield from the rCMVLUC-infected HFF cells was determined by the immunofluorescence assay using human antiserum to HCMV after 5-7 days incubation in the presence of various concentrations of the drug.