Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization.

Article Details

Citation

Copy to clipboard

Deng JZ, McMasters DR, Rabbat PM, Williams PD, Coburn CA, Yan Y, Kuo LC, Lewis SD, Lucas BJ, Krueger JA, Strulovici B, Vacca JP, Lyle TA, Burgey CS

Development of an oxazolopyridine series of dual thrombin/factor Xa inhibitors via structure-guided lead optimization.

Bioorg Med Chem Lett. 2005 Oct 15;15(20):4411-6.

PubMed ID

16137886 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
2-(6-CHLORO-3-{[2,2-DIFLUORO-2-(1-OXIDO-2-PYRIDINYL)ETHYL]AMINO}-2-OXO-1(2H)-PYRAZINYL)-N-[(2-FLUOROPHENYL)METHYL]ACETAMIDE	Prothrombin	Ki (nM)	2.3	N/A	N/A	Details
N7-BUTYL-N2-(5-CHLORO-2-METHYLPHENYL)-5-METHYL[1,2,4]TRIAZOLO[1,5-A]PYRIMIDINE-2,7-DIAMINE	Prothrombin	IC 50 (nM)	1000	N/A	N/A	Details