title: Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors.
abstract: We report on an extensive structure-activity relationship study of novel PI4K IIIβ inhibitors. The purine derivative of the potent screening hit T-00127-HEV1 has served as a suitable starting point for a thorough investigation of positions 8 and 2. While position 8 of the purine scaffold can only bear a small substituent to maintain the inhibitory activity, position 2 is opened for extensive modification and can accommodate even substituted phenyl rings without the loss of PI4K IIIβ inhibitory activity. These empirical observations nicely correlate with the results of our docking study, which suggests that position 2 directs towards solution and can provide the necessary space for the interaction with remote residues of the enzyme, whereas the cavity around position 8 is strictly limited. The obtained compounds have also been subjected to antiviral screening against a panel of (+)ssRNA viruses.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Kögler
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Plačková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; Department of Chemistry of Natural Compounds, Institute of Chemical Technology Prague, Technická 5, Prague 166 28, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mejdrová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Eliška
authors.initials: E
authors.lastname: Procházková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Strunin
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Weber
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Mertlíková-Kaiserová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Gilead Sciences & IOCB Research Centre, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D029822:Enterovirus B, Human / Q000187:drug effects*; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D011687:Purines; C581087:PI4KB protein, human; C030985:purine
keywords: Antiviral agent; Hepatitis C virus; PI4K IIIβ; Phosphatidylinositol 4-kinase; Purine