Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies.
Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies.
复制标题
DOI：
10.1021/jm2001426
复制
发表时间：
2011-08-25
影响因子：
7.3
通讯作者：
McKenna CE
中科院分区：
文献类型：
--
作者：
Zakharova VM;Serpi M;Krylov IS;Peterson LW;Breitenbach JM;Borysko KZ;Drach JC;Collins M;Hilfinger JM;Kashemirov BA;McKenna CE
Eight novel single amino acid (6–11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPCa, 4) and its cyclic adenine analog ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC50 values for the prodrugs vs vaccinia, cowpox, human cytomegalo- and herpes simplex type 1 viruses were similar to those for the parent drugs ((S)-HPMPC, 2, (S)-HPMPA, 1; IC50 0.3 – 30 µM); there were no cytoxicity with KB or HFF cells at ≤ 100 µM. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30 – 1732 min) with differences of 3–10× between phostonate diastereomers. The tyrosine-alkylamide derivatives of 3 and 4 were the most stable. (L)-Tyr-NHiBu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39 % vs <5 %).
登录
查看更多内容
影响因子：
4.9
作者：
Eriksson, Ulrika;Peterson, Larryn W.;McKenna, Charles E.
通讯作者：
McKenna, Charles E.
影响因子：
2.3
作者：
McKenna, CE;Kashemirov, BA;Hilfinger, JM
通讯作者：
Hilfinger, JM
影响因子：
1.8
作者：
Katsuta, Ryo;Shibata, Chie;Kitahara, Takeshi
通讯作者：
Kitahara, Takeshi
影响因子：
15
作者：
NELSON, KA;BENTRUDE, WG;HUTCHINSON, JP
通讯作者：
HUTCHINSON, JP
影响因子：
3.7
作者：
Buller, RM;Owens, G;Hostetler, KY
通讯作者：
Hostetler, KY