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

2012; American Chemical Society; Volume: 55; Issue: 20 Linguagem: Inglês

10.1021/jm3010459

1520-4804

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,

Pneumocystis jirovecii pneumonia detection and treatment

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.