Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis

Tianbao Lu; Thomas Markotan; Frank Coppo; Bruce Tomczuk; Carl Crysler; Stephen Eisennagel; John Spurlino; Lisa Gremminger; Richard M Soll; Edward C Giardino; Roger Bone

doi:10.1016/j.bmcl.2004.05.002

Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis

Bioorg Med Chem Lett. 2004 Jul 16;14(14):3727-31. doi: 10.1016/j.bmcl.2004.05.002.

Authors

Tianbao Lu¹, Thomas Markotan, Frank Coppo, Bruce Tomczuk, Carl Crysler, Stephen Eisennagel, John Spurlino, Lisa Gremminger, Richard M Soll, Edward C Giardino, Roger Bone

Affiliation

¹ 3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Exton, PA 19341, USA. tlu3@prdus.jnj.com

PMID: 15203151
DOI: 10.1016/j.bmcl.2004.05.002

Abstract

Through structure-based drug design and parallel synthesis, we have discovered a novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as guanidine bioisosteres. These compounds have been found to be highly potent, highly selective, and orally bioavailable.

MeSH terms

Administration, Oral
Animals
Anticoagulants / chemical synthesis*
Anticoagulants / pharmacokinetics
Binding Sites
Cell Line
Crystallography, X-Ray
Dogs
Drug Design*
Guanidines / chemical synthesis*
Guanidines / pharmacokinetics
Humans
Serine Proteinase Inhibitors / chemical synthesis
Serine Proteinase Inhibitors / pharmacokinetics
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*

Substances

Anticoagulants
Guanidines
Serine Proteinase Inhibitors
Thrombin