Drug discovery of human immunodeficiency virus (HIV) is a hot field in medicinal chemistry community for many years. The diarylpyrimidines (DAPYs) are the second‐generation non‐nucleoside reverse transcriptase inhibitors (NNRTIs) targeting reverse transcriptase, playing a great irreplaceable role in HIV transcriptional therapy. However, fast‐growing drug‐resistant mutations as nonnegligible challenge are still unpredictably appeared in the clinical practice, leading to deactivate or reduce the existing drugs. In the last 20 years, more and more novel DAPY derivatives have developed with the purpose to counter the mutants. Nevertheless, most of them have dissatisfactory pharmacokinetics (PK) or poor antiviral activity toward resistant mutant strains. In this article, we will analyze the NNRTI derivatives with promising druggability, and summarize a series of druggability modification strategies to improve the antiviral activity, reduce toxicity and improve the PK properties in recent years. The prospects of DAPYs and the directions for future efforts will be discussed.

中文翻译：

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二芳基嘧啶型非核苷逆转录酶抑制剂的成药性修饰策略

人类免疫缺陷病毒（HIV）的药物发现多年来一直是药物化学界的热门领域。二芳基嘧啶（DAPYs）是靶向逆转录酶的第二代非核苷逆转录酶抑制剂（NNRTIs），在HIV转录治疗中发挥着不可替代的作用。然而，快速增长的耐药突变作为不可忽视的挑战在临床实践中仍然不可预测地出现，导致现有药物停用或减少。在过去的 20 年里，越来越多的新型 DAPY 衍生物被开发出来，旨在对抗突变体。然而，它们中的大多数具有不令人满意的药代动力学 (PK) 或对耐药突变株的抗病毒活性较差。在本文中，我们将分析具有良好成药性的 NNRTI 衍生物，并总结了近年来一系列提高抗病毒活性、降低毒性和改善PK特性的成药性修饰策略。将讨论 DAPY 的前景和未来努力的方向。