CONJUGATES OF INHIBITORS OF HIV SPECIFIC ENZYMES W/ STEROID DERIVATIVES

在发现和发现方面已经取得了重大进展 在艾滋病几个关键阶段发挥作用的抗艾滋病毒药物的发展 病毒的生命周期。尽管取得了进展，但临床疗效 HIV特异性酶、逆转录酶(RT)和 蛋白水解酶(P)，在细胞学方面仍有待改进 生物利用度、毒性和交叉艾滋病毒耐药性。这项建议 通过三种药物结合实现这些改进的尝试 方法论。(1)HIV-RT抑制剂AZT的合成 类固醇抗药。这可能会增加抑制剂的亲脂性， 细胞渗透性和半衰期。类固醇对人体的影响 结合物的破坏应该没有全身副作用。 (2)AZT与甾体型磷三酸酯结合物的制备。 它们可以实现生物利用度的优势以及更多 结合物断裂时形成活化的药物。(3)共轭 AZT和一种有效的HIV-P抑制剂环状尿素。这不可能 IMP不仅提高了细胞的生物利用度，减少了毒性，而且 通过释放HIV-RT和HIV-P来减少交叉耐药性 缓蚀剂，达到协同效应。这些措施的结果 调查将对结构特征有深入的了解 提供了一个合理的基础 开发更有效的抗艾滋病毒药物。

Significant progress has been made toward discovery and development of anti-HIV agents acting at several critical stages of the viral life cycle. Despite the advances, clinical efficiency of inhibitors of HIV specific enzymes, reverse transcriptase (RT) and protease (P), remains to be improved in terms of cellular bio-availability, toxicities and cross HIV resistance. This proposal attempts to achieve these improvements by three drug conjugation methodologies. (1) Synthesis of an HIV-RT inhibitor, AZT, with steroid antidrugs. This could increase the inhibitor's lipophilicity, permeability into cell and half life. The steroid moiety upon breakage of the conjugate should be free of systemic side effects. (2) Preparation of AZT conjugates with steroidal phophotriesters. They could achieve the bio-availability advantages as well as a more activated drug form upon breakage of the conjugate. (3) Conjugation of AZT and a potent HIV-P inhibitor, a cyclic urea. This could not only imp rove cellular bioavailability, reduce toxicities, but also diminish the cross resistance by releasing a HIV-RT and a HIV-P inhibitor, achieving a synergistic effect. Results of these investigations will yield insight into the structural characteristics of conjugates with a promise of providing a rational basis for the development of more efficient anti-HIV agents.