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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Johns BA,Kawasuji T,Weatherhead JG,Taishi T,Temelkoff DP,Yoshida H,Akiyama T,Taoda Y,Murai H,Kiyama R,Fuji M,Tanimoto N,Jeffrey J,Foster SA,Yoshinaga T,Seki T,Kobayashi M,Sato A,Johnson MN,Garvey EP,Fujiwara Tdoi
10.1021/jm400645wsubject
Has Abstractpub_date
2013-07-25 00:00:00pages
5901-16issue
14eissn
0022-2623issn
1520-4804journal_volume
56pub_type
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