|
Authors
|
 |
B.Ye,
D.O.Arnaiz,
Y.L.Chou,
B.D.Griedel,
R.Karanjawala,
W.Lee,
M.M.Morrissey,
K.L.Sacchi,
S.T.Sakata,
K.J.Shaw,
S.C.Wu,
Z.Zhao,
M.Adler,
S.Cheeseman,
W.P.Dole,
J.Ewing,
R.Fitch,
D.Lentz,
A.Liang,
D.Light,
J.Morser,
J.Post,
G.Rumennik,
B.Subramanyam,
M.E.Sullivan,
R.Vergona,
J.Walters,
Y.X.Wang,
K.A.White,
M.Whitlow,
M.J.Kochanny.
|
|
There remains a high unmet medical need for a safe oral therapy for thrombotic
disorders. The serine protease factor Xa (fXa), with its central role in the
coagulation cascade, is among the more promising targets for anticoagulant
therapy and has been the subject of intensive drug discovery efforts.
Investigation of a hit from high-throughput screening identified a series of
thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead
optimization by incorporation of hydrophilic groups led to the discovery of
compounds with picomolar inhibitory potency and micromolar in vitro
anticoagulant activity. Based on their high potency, selectivity, oral
pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis,
compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced
into development.
|