Stereospecific synthesis, structure-activity relationship, and oral bioavailability of tetrahydropyrimidin-2-one HIV protease inhibitors

被引:59
作者
De Lucca, GV [1 ]
Liang, J [1 ]
De Lucca, I [1 ]
机构
[1] DuPont Pharmaceut Co, Wilmington, DE 19880 USA
关键词
D O I
10.1021/jm9803626
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The use of tetrahydropyrimidinones as an alternate scaffold for designing HIVPR inhibitors has advantages, over the previously disclosed hexahydro-1,3-diazepin-2-ones, of being more unsymmetrical (different P1/P1'), less crystalline, more soluble, and more lipophilic (mono-ol vs diol). They show a better translation of K-i to IC90 for the more polar P2 groups that in general give the more potent enzyme inhibitors. Structure-activity relationship (SAR) studies of the tetrahydropyrimidinones showed that the phenylethyl P1' substituent, the hydroxyl group, and the urea carbonyl are all critical for good activity. However, there was significant flexibility in the possible P2/P2' substituents that could be used. Many analogues that contained identical or different P2/P2' substituents, or only one P2 substituent, were found to have excellent enzyme potency and several had excellent antiviral potency. Several of these compounds were examined for oral bioavailability in the rat or the dog at 10 mg/kg. However, the oral bioavailability of the tetrahydropyrimidinones was, in general, less than the corresponding hexahydro-1,3-diazepin-2-ones. Unfortunately, when all factors are considered, including potency, protein binding, solubility, bioavailability, and resistance profile, the tetrahydropyrimidinones did not offer any advantage over the previously disclosed hexahydro-1,3-diazepin-2-ones series.
引用
收藏
页码:135 / 152
页数:18
相关论文
共 38 条
  • [1] AN ASSAY FOR HIV RNA IN INFECTED CELL LYSATES, AND ITS USE FOR THE RAPID EVALUATION OF ANTIVIRAL EFFICACY
    BACHELER, LT
    PAUL, M
    OTTO, MJ
    JADHAV, PK
    STONE, BA
    MILLER, JA
    [J]. ANTIVIRAL CHEMISTRY & CHEMOTHERAPY, 1994, 5 (02) : 111 - 121
  • [2] Boehme RE, 1995, ANNU REP MED CHEM, V30, P139
  • [3] CHONG KT, 1996, EXPERT OPIN INV DRUG, V5, P115
  • [4] Darke P L, 1994, Adv Pharmacol, V25, P399, DOI 10.1016/S1054-3589(08)60438-X
  • [5] De Lucca G V, 1998, Pharm Biotechnol, V11, P257
  • [6] Stereospecific, stereoselective rearrangement of hexahydro-1,3-diazepin-2-ones to tetrahydropyrimidin-2-ones and imidazolidin-2-ones, a useful route for the synthesis of HIV protease inhibitors
    De Lucca, GV
    [J]. JOURNAL OF ORGANIC CHEMISTRY, 1998, 63 (14) : 4755 - 4766
  • [7] Nonsymmetric P2/P2′ cyclic urea HIV protease inhibitors.: Structure-activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues
    De Lucca, GV
    Kim, UT
    Liang, J
    Cordova, B
    Klabe, RM
    Garber, S
    Bacheler, LT
    Lam, GN
    Wright, MR
    Logue, KA
    Erickson-Viitanen, S
    Ko, SS
    Trainor, GL
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (13) : 2411 - 2423
  • [8] TOWARD IMPROVED ANTI-HIV CHEMOTHERAPY - THERAPEUTIC STRATEGIES FOR INTERVENTION WITH HIV-INFECTIONS
    DECLERCQ, E
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (14) : 2491 - 2517
  • [9] Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule
    DeLucca, GV
    EricksonViitanen, S
    Lam, PYS
    [J]. DRUG DISCOVERY TODAY, 1997, 2 (01) : 6 - 18
  • [10] Synthesis and evaluation of delta lactams as nonpeptide HIV-protease inhibitors
    DeLucca, GV
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (05) : 501 - 504