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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)
We report herein the discovery of
the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors
dolutegravir (S/GSK1349572) (<b>3</b>) and S/GSK1265744 (<b>4</b>). 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 <b>3</b> and <b>4</b>, which
are currently in clinical development