Subbaiah Murugaiah A M, Meanwell Nicholas A, Kadow John F
Prodrug Group, Department of Medicinal Chemistry, Biocon Bristol-Myers Squibb R&D Centre, Biocon Park, Bommasandra Phase IV, Jigani Link Road, Bangalore 560009, India.
Department of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ, 08543-4000, USA.
Eur J Med Chem. 2017 Oct 20;139:865-883. doi: 10.1016/j.ejmech.2017.07.044. Epub 2017 Jul 22.
Combination antiretroviral therapy (cART) is currently the most effective treatment for HIV-1 infection. HIV-1 protease inhibitors (PIs) are an important component of some regimens of cART. However, PIs are known for sub-optimal ADME properties, resulting in poor oral bioavailability. This often necessitates high drug doses, combination with pharmacokinetic enhancers and/or special formulations in order to effectively deliver PIs, which may lead to a high pill burden and reduced patient compliance. As a remedy, improving the ADME properties of existing drugs via prodrug and other approaches has been pursued in addition to the development of next generation PIs with improved pharmacokinetic, resistance and side effect profiles. Phosphate prodrugs have been explored to address the solubility-limiting absorption and high excipient load. Prodrug design to target carrier-mediated drug delivery has also been explored. Amino acid prodrugs have been shown to improve permeability by engaging active transport mechanisms, reduce efflux and mitigate first pass metabolism while acyl migration prodrugs have been shown to improve solubility. Prodrug design efforts have led to the identification of one marketed agent, fosamprenavir, and clinical studies with two other prodrugs. Several of the reported approaches lack detailed in vivo characterization and hence the potential preclinical or clinical benefits of these approaches are yet to be fully determined.
联合抗逆转录病毒疗法（cART）是目前治疗HIV-1感染最有效的方法。HIV-1蛋白酶抑制剂（PIs）是cART某些治疗方案的重要组成部分。然而，PIs的吸收、分布、代谢和排泄（ADME）特性欠佳，导致口服生物利用度较低。这通常需要高剂量用药，联合药代动力学增强剂和/或特殊制剂以有效递送PIs，这可能会导致高 pill负担并降低患者依从性。作为一种补救措施，除了开发具有改善药代动力学、耐药性和副作用特征的下一代PIs外，还通过前药和其他方法来改善现有药物的ADME特性。人们已经探索了磷酸前药来解决溶解度限制吸收和高辅料负荷的问题。还探索了针对载体介导药物递送的前药设计。氨基酸前药已被证明可通过参与主动转运机制来提高通透性、减少外排并减轻首过代谢，而酰基迁移前药已被证明可提高溶解度。前药设计工作已导致一种上市药物福沙普那韦的鉴定，以及另外两种前药的临床研究。一些已报道的方法缺乏详细的体内表征，因此这些方法的潜在临床前或临床益处尚未完全确定。
