Carbamoyl Pyridone HIV-1 Integrase Inhibitors. 1. Molecular Design and Establishment of an Advanced Two-Metal Binding Pharmacophore

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• 作者：Takashi Kawasuji ; Brian A. Johns ; Hiroshi Yoshida ; Teruhiko Taishi ; Yoshiyuki Taoda ; Hitoshi Murai ; Ryuichi Kiyama ; Masahiro Fuji ; Tomokazu Yoshinaga ; Takahiro Seki ; Masanori Kobayashi ; Akihiko Sato ; Tamio Fujiwara
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 25, 2012
• 年：2012
• 卷：55
• 期：20
• 页码：8735-8744
• 全文大小：401K
• 年卷期：v.55,no.20(October 25, 2012)
• ISSN：1520-4804

文摘

Our group has focused on expanding the scope of a two-metal binding pharmacophore concept to explore HIV-1 integrase inhibitors through medicinal chemistry efforts to design novel scaffolds which allow for improvement of pharmacokinetic (PK) and resistance profiles. A novel chelating scaffold was rationally designed to effectively coordinate two magnesium cofactors and to extend an aromatic group into an optimal hydrophobic pharmacophore space. The new chemotype, consisting of a carbamoyl pyridone core unit, shows high inhibitory potency in both enzymatic and antiviral assay formats with low nM IC₅₀ and encouraging potency shift effects in the presence of relevant serum proteins. The new inhibitor design displayed a remarkable PK profile suggestive of once daily dosing without the need for a PK booster as demonstrated by robust drug concentrations at 24 h after oral dosing in rats, dogs, and cynomolgus monkeys.