Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles
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- 作者：Takashi Kawasuji ; Brian A. Johns ; Hiroshi Yoshida ; Jason G. Weatherhead ; Toshiyuki Akiyama ; Teruhiko Taishi ; Yoshiyuki Taoda ; Minako Mikamiyama-Iwata ; Hitoshi Murai ; Ryuichi Kiyama ; Masahiro Fuji ; Norihiko Tanimoto ; Tomokazu Yoshinaga ; Takahiro Seki ; Masanori Kobayashi ; Akihiko Sato ; Edward P. Garvey ; Tamio Fujiwara
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：February 14, 2013
- 年：2013
- 卷：56
- 期：3
- 页码：1124-1135
- 全文大小：432K
- 年卷期：v.56,no.3(February 14, 2013)
- ISSN：1520-4804
文摘
This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.