title: Carbamoyl pyridone HIV-1 integrase inhibitors. 1. Molecular design and establishment of an advanced two-metal binding pharmacophore.
abstract: 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.
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan. takashi.kawasuji@shionogi.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasuji
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Taishi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Taoda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Murai
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kiyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fuji
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshinaga
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002413:Cations, Divalent; D002460:Cell Line; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D019429:Integrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008274:Magnesium / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D011728:Pyridones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats
chemical_list: D000998:Antiviral Agents; D002413:Cations, Divalent; D002614:Chelating Agents; D019429:Integrase Inhibitors; D011728:Pyridones; D008274:Magnesium