Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs
Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) prodrugs
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DOI：
10.1177/095632029700800610
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发表时间：
1997-11-01
影响因子：
--
通讯作者：
Bischofberger, N
中科院分区：
文献类型：
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作者：
Arimilli, MN;Kim, CU;Bischofberger, N
评价了抗逆转录病毒制剂9-[2-(膦甲氧基)丙基]腺嘌呤(PMPA)的潜在口服生物利用度前药。将PMPA与相应的烷基氯甲基碳酸酯和N-烷基氯甲基氨基甲酸酯试剂进行烷基化反应，合成了烷基氨基甲酸甲酯。除了化学稳定性和酶稳定性外，还对前药的体外抗病毒活性进行了评估。与PMPA相比，碳酸酯前药对人类免疫缺陷病毒1型(HIV-1)毒株IIIB在MT-2细胞中复制的抑制作用增强了2.5-500倍。除碳酸叔丁酯外，其它烷基甲基碳酸酯在pH值为2.2和7.4时具有较好的化学稳定性，但在狗血浆存在下可迅速转化为相应的PMPA单酯。N-叔丁基氨基甲酸甲酯等烷基氨基甲酸甲酯前药具有较高的体外稳定性。基于其化学稳定性和良好的口服生物利用度，双(POC)PMPA(异丙基碳酸甲酯)被选为临床候选药物。
Potentially orally bioavailable prodrugs of the antiretroviral agent 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) were evaluated. Alkyl methyl carbamates were synthesized by alkylation of PMPA with the corresponding alkyl chloromethyl carbonate and N-alkyl chloromethyl carbamate reagents. The prodrugs were evaluated for in vitro antiviral activity in addition to chemical and enzymic stability. The inhibition of human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-2 cells by the carbonate prodrugs was found to be 2.5-500-fold increased compared to PMPA. The alkyl methyl carbonates, except t-butyl methyl carbonate, had reasonable chemical stability at pH 2.2 and 7.4, but were rapidly converted to the corresponding monoester of PMPA in the presence of dog plasma. The alkyl methyl carbamate prodrugs such as N-t-butyl methyl carbamate were found to have high stability in vitro. Based on its chemical stability and good oral bioavailability, bis(POC)PMPA (isopropyl methyl carbonate) was chosen as a clinical candidate.