Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)
Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)
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DOI：
10.1021/jm400645w
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发表时间：
2013-07-25
影响因子：
7.3
通讯作者：
Fujiwara, Tamio
中科院分区：
文献类型：
--
作者：
Johns, Brian A.;Kawasuji, Takashi;Fujiwara, Tamio
我们在此报告发现了人类免疫缺陷病毒1型（HIV-1）整合酶抑制剂度鲁特韦（S/GSK 1349572）（3）和S/GSK 1265744（4）。这些药物源自一系列使用整合酶催化活性位点的双金属螯合模型设计的氨基甲酰基吡啶酮类似物。结构-活性研究开发了三环系列的氨基甲酰基吡啶，其表现出指示每日一次给药的性质和对耐药病毒株的上级效力。三环氨基甲酰基吡啶酮骨架内固有的半缩醛胺环融合立体中心导致关键的底物控制的非对映选择性合成策略，由此采用来自小的容易获得的氨基醇的手性信息来控制最终药物候选物的相对和绝对立体化学。根据环的大小和立构中心的位置，观察到中度到极高水平的立体化学控制。这种方法导致了3和4的发现，目前正在临床开发中。
We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereo-selective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.