Synthesis and biological activation of an ethylene glycol-linked amino acid conjugate of cyclic cidofovir

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• 作者：Ulrika Eriksson ; John M. Hilfinger ; Jae-Seung Kim ; Stefanie Mitchell ; Paul Kijek ; Katherine Z. Borysko ; Julie M. Breitenbach ; John C. Drach ; Boris A. Kashemirov ; Charles E. McKenna
• 关键词：Prodrug ; cHPMPC ; HPMPC ; Biotransformation ; HCMV ; Anti-viral ; Biodefense
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 出版时间：1 February 2007
• 年：2007
• 卷：17
• 期：3
• 页码：583-586
• 全文大小：147 K

文摘

Cidofovir (HPMPC) is a broad-spectrum anti-viral agent whose potential, particularly in biodefense scenarios, is limited by its low oral bioavailability. Two prodrugs (3 and 4) created by conjugating ethylene glycol-linked amino acids (L-Val, L-Phe) with the cyclic form of cidofovir (cHPMPC) via a P–O ester bond were synthesized and their pH-dependent stability (3 and 4), potential for in vivo reconversion to drug (3), and oral bioavailability (3) were evaluated. The prodrugs were stable in buffer between pH 3 and 5, but underwent rapid hydrolysis in liver (t_1/2 = 3.7 min), intestinal (t_1/2 = 12.5 min), and Caco-2 cell homogenates (t_1/2 = 20.2 min). In vivo (rat), prodrug 3 was >90 % reconverted to cHPMPC. The prodrug was 4× more active than ganciclovir (IC₅₀ value, 0.68 μM vs 3.0 μM) in a HCMV plaque reduction assay. However, its oral bioavailability in a rat model was similar to the parent drug. The contrast between the promising activation properties and unenhanced transport of the prodrug is briefly discussed.