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)

J Med Chem. 2013 Jul 25;56(14):5901-16. doi: 10.1021/jm400645w.

Brian A Johns ¹, Takashi Kawasuji, Jason G Weatherhead, Teruhiko Taishi, David P Temelkoff, Hiroshi Yoshida, Toshiyuki Akiyama, Yoshiyuki Taoda, Hitoshi Murai, Ryuichi Kiyama, Masahiro Fuji, Norihiko Tanimoto, Jerry Jeffrey, Scott A Foster, Tomokazu Yoshinaga, Takahiro Seki, Masanori Kobayashi, Akihiko Sato, Matthew N Johnson, Edward P Garvey, Tamio Fujiwara

Affiliations

Affiliation

1 GlaxoSmithKline Research & Development , Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States.

PMID: 23845180 DOI: 10.1021/jm400645w

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.

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