Shandong University, School of Pharmaceutical Sciences, Department of Medicinal Chemistry, 44, West Culture Road, 250012 Jinan, Shandong, PR China.
Expert Opin Ther Pat. 2011 May;21(5):717-96. doi: 10.1517/13543776.2011.568481. Epub 2011 Apr 4.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) form the backbone of antiretroviral treatment for many HIV-infected individuals. The unique antiviral activity, high specificity and low toxicity associated with this class of agents make them a frequent choice for first-line therapy. However, the effectiveness of NNRTI drugs can be hampered by the rapid emergence of drug-resistant viruses, poor pharmacokinetic (PK) properties and severe side effects in long-term usage. Therefore, there is an urgent need to develop novel NNRTIs without such limitations. An analysis of this vast group of already existing inhibitors should constitute the basis of the effort toward the development of more potent, promising drugs or candidates.
The present review provides an overview of NNRTI research from 2005 to 2010, and highlights some important medicinal chemistry principles and strategies in the development of NNRTIs.
An in-depth analysis of the common binding configuration and structural features of NNRTIs, as well as the underlying clues to the 'follow-on'-based chemical evolution efforts (including the key medicinal chemistry principles and strategies: bioisosteric replacement, molecular hybridization, scaffold hopping, prodrug, etc.) has greatly accelerated the optimization of the pharmacodynamic (PD) and PK profiles. There is still a good deal of opportunity to discover new highly potent NNRTIs or novel scaffolds with unconventional mechanisms for reverse transcriptase (RT) inhibition.
非核苷类逆转录酶抑制剂（NNRTIs）是许多 HIV 感染者抗逆转录病毒治疗的基础。该类药物具有独特的抗病毒活性、高度特异性和低毒性，因此常被用作一线治疗药物。然而，NNRTI 药物的有效性可能会受到耐药病毒的迅速出现、较差的药代动力学（PK）特性和长期使用的严重副作用的影响。因此，迫切需要开发没有这些限制的新型 NNRTIs。对这一大类已有的抑制剂进行分析，应该是开发更有效、更有前途的药物或候选药物的基础。
本综述提供了 2005 年至 2010 年 NNRTI 研究的概述，并强调了开发 NNRTIs 过程中的一些重要的药物化学原理和策略。
深入分析 NNRTIs 的常见结合构象和结构特征，以及基于“后续”的化学进化努力的潜在线索（包括关键的药物化学原理和策略：生物等排体替换、分子杂交、骨架跃迁、前药等），极大地加速了药效学（PD）和 PK 特征的优化。仍然有很大的机会发现新的、具有非传统逆转录酶（RT）抑制机制的高度有效的 NNRTIs 或新型骨架。
