Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization.
Thrombin-inhibitor X-ray crystal structures, in combination with the installation of binding elements optimized within the pyrazinone series of thrombin inhibitors, were utilized to transform a weak triazolopyrimidine lead into a series of potent oxazolopyridines. A modification intended to attenuate plasma protein binding (i.e., conversion of the P3 pyridine to a piperidine) conferred significant factor Xa activity to this series. Ultimately, these dual thrombin/factor Xa inhibitors demonstrated excellent in vitro and in vivo anticoagulant efficacy.
Deng
James Z
JZ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
McMasters
Daniel R
DR
Rabbat
Philippe M A
PM
Williams
Peter D
PD
Coburn
Craig A
CA
Yan
Youwei
Y
Kuo
Lawrence C
LC
Lewis
S Dale
SD
Lucas
Bobby J
BJ
Krueger
Julie A
JA
Strulovici
Berta
B
Vacca
Joseph P
JP
Lyle
Terry A
TA
Burgey
Christopher S
CS
D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*
D000991:Antithrombins; D065427:Factor Xa Inhibitors; D011725:Pyridines