title: Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles.
abstract: 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.
authors: Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd. , 3-1-1, Osaka 561-0825, Japan. takashi.kawasuji@shionogi.co.jp
authors: Takashi
authors: T
authors: Kawasuji
authors: Brian A
authors: BA
authors: Johns
authors: Hiroshi
authors: H
authors: Yoshida
authors: Jason G
authors: JG
authors: Weatherhead
authors: Toshiyuki
authors: T
authors: Akiyama
authors: Teruhiko
authors: T
authors: Taishi
authors: Yoshiyuki
authors: Y
authors: Taoda
authors: Minako
authors: M
authors: Mikamiyama-Iwata
authors: Hitoshi
authors: H
authors: Murai
authors: Ryuichi
authors: R
authors: Kiyama
authors: Masahiro
authors: M
authors: Fuji
authors: Norihiko
authors: N
authors: Tanimoto
authors: Tomokazu
authors: T
authors: Yoshinaga
authors: Takahiro
authors: T
authors: Seki
authors: Masanori
authors: M
authors: Kobayashi
authors: Akihiko
authors: A
authors: Sato
authors: Edward P
authors: EP
authors: Garvey
authors: Tamio
authors: T
authors: Fujiwara
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011728:Pyridones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
chemical_list: D019428:HIV Integrase Inhibitors; D011728:Pyridones; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1