4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species

被引:83
作者
Summa, Vincenzo
Petrocchi, Alessia
Matassa, Victor G.
Gardelli, Cristina
Muraglia, Ester
Rowley, Michael
Paz, Odalys Gonzalez
Laufer, Ralph
Monteagudo, Edith
Pace, Paola
机构
[1] IRBM MRL Rome, Dept Med Chem, I-00040 Monte Porzio Catone, Italy
[2] IRBM MRL Rome, Dept Drug Metab, I-00040 Monte Porzio Catone, Italy
关键词
D O I
10.1021/jm060854f
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.
引用
收藏
页码:6646 / 6649
页数:4
相关论文
共 15 条
[1]   SYNTHESIS OF 5,6-DIHYDROXY-2-PHENYL-4-PYRIMIDINECARBOXYLIC ACID, METHYL-ESTER, A CORRECTED STRUCTURE [J].
CULBERTSON, TP .
JOURNAL OF HETEROCYCLIC CHEMISTRY, 1979, 16 (07) :1423-1424
[2]   Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes [J].
Grobler, JA ;
Stillmock, K ;
Hu, BH ;
Witmer, M ;
Felock, P ;
Espeseth, AS ;
Wolfe, A ;
Egbertson, M ;
Bourgeois, M ;
Melamed, J ;
Wai, JS ;
Young, S ;
Vacca, J ;
Hazuda, DJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (10) :6661-6666
[3]   Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase [J].
Hazuda, DJ ;
Felock, PJ ;
Hastings, JC ;
Pramanik, B ;
Wolfe, AL .
JOURNAL OF VIROLOGY, 1997, 71 (09) :7005-7011
[4]   A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase [J].
Hazuda, DJ ;
Anthony, NJ ;
Gomez, RP ;
Jolly, SM ;
Wai, JS ;
Zhuang, LH ;
Fisher, TE ;
Embrey, M ;
Guare, JP ;
Egbertson, MS ;
Vacca, JP ;
Huff, JR ;
Felock, PJ ;
Witmer, MV ;
Stillmock, KA ;
Danovich, R ;
Grobler, J ;
Miller, MD ;
Espeseth, AS ;
Jin, LX ;
Chen, IW ;
Lin, JH ;
Kassahun, K ;
Ellis, JD ;
Wong, BK ;
Xu, W ;
Pearson, PG ;
Schleif, WA ;
Cortese, R ;
Emini, E ;
Summa, V ;
Holloway, MK ;
Young, SD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (31) :11233-11238
[5]   Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells [J].
Hazuda, DJ ;
Felock, P ;
Witmer, M ;
Wolfe, A ;
Stillmock, K ;
Grobler, JA ;
Espeseth, A ;
Gabryelski, L ;
Schleif, W ;
Blau, C ;
Miller, MD .
SCIENCE, 2000, 287 (5453) :646-650
[6]   Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques [J].
Hazuda, DJ ;
Young, SD ;
Guare, JP ;
Anthony, NJ ;
Gomez, RP ;
Wai, JS ;
Vacca, JP ;
Handt, L ;
Motzel, SL ;
Klein, HJ ;
Dornadula, G ;
Danovich, RM ;
Witmer, MV ;
Wilson, KAA ;
Tussey, L ;
Schleif, WA ;
Gabryelski, LS ;
Jin, LX ;
Miller, MD ;
Casimiro, DR ;
Emini, EA ;
Shiver, JW .
SCIENCE, 2004, 305 (5683) :528-532
[7]   Design, synthesis, and SAR studies of novel and highly active tri-cyclic HIV integrase inhibitors [J].
Jin, Haolun ;
Cai, Ruby Z. ;
Schacherer, Laura ;
Jabri, Salman ;
Tsiang, Manuel ;
Fardis, Maria ;
Chen, Xiaowu ;
Chen, James M. ;
Kim, Choung U. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (15) :3989-3992
[8]   2-(2-thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: Discovery, SAR, modeling, and mutagenesis [J].
Koch, U ;
Attenni, B ;
Malancona, S ;
Colarusso, S ;
Conte, I ;
Di Filippo, M ;
Harper, S ;
Pacini, B ;
Giomini, C ;
Thomas, S ;
Incitti, I ;
Tomei, L ;
De Francesco, R ;
Altamura, S ;
Matassa, VG ;
Narjes, F .
JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (05) :1693-1705
[9]   The monoethyl ester of meconic acid is an active site inhibitor of HCVNS5B RNA-dependent RNA polymerase [J].
Pace, P ;
Nizi, E ;
Pacini, B ;
Pesci, S ;
Matassa, V ;
De Francesco, R ;
Altamura, S ;
Summa, V .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (12) :3257-3261
[10]  
RAMIREZ M, 2006, 10 EUR AIDS C DUBL I