title: Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744).
abstract: We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.
authors.affiliation: GlaxoSmithKline Research & Development , Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Johns
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasuji
authors.forename: Jason G
authors.initials: JG
authors.lastname: Weatherhead
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Taishi
authors.forename: David P
authors.initials: DP
authors.lastname: Temelkoff
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Akiyama
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: Norihiko
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Jerry
authors.initials: J
authors.lastname: Jeffrey
authors.forename: Scott A
authors.initials: SA
authors.lastname: Foster
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: Matthew N
authors.initials: MN
authors.lastname: Johnson
authors.forename: Edward P
authors.initials: EP
authors.lastname: Garvey
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D004285:Dogs; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis*; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099226:Dolutegravir; D054659:Diketopiperazines
chemical_list: D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir; C584914:cabotegravir; D054659:Diketopiperazines