Merck Frosst Centre for Therapeutic Research , Kirkland, QC Canada.
Department of Process Chemistry, Merck & Co., Inc., Rahway, NJ 07065.
J Med Chem. 2015 Oct 22;58(20):8154-65. doi: 10.1021/acs.jmedchem.5b01037. Epub 2015 Oct 8.
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
寻找新的分子结构，这些结构类似于 HIV 整合酶链转移抑制所需的关键双金属结合药效团，是药物发现中一个充满活力的研究领域。在这里，我们介绍了一类基于 MK-0536 的 2-吡啶酮核心的新型 HIV 整合酶链转移抑制剂的发现。这些努力导致了两种具有优异抗病毒活性和临床前药代动力学特征的先导化合物的鉴定，以支持每天一次的人体剂量预测。在狗中进行的剂量递增 PK 研究表明，口服吸收有限存在重大问题，需要采用创新的前药策略来提高母体分子的高剂量血浆暴露量。
