Molecular design and structure--activity relationships leading to the potent, selective, and orally active thrombin active site inhibitor BMS-189664.

Abstract

A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.

• Authors: Jagabandhu Das, S David Kimball, Steven E Hall, Wen Ching Han, Edwin Iwanowicz, James Lin, Robert V Moquin, Joyce A Reid, John S Sack, Mary F Malley, Chiehying Y Chang, Saeho Chong, David B Wang-Iverson, Daniel G M Roberts, Steven M Seiler, William A Schumacher, Martin L Ogletree
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 12 Issue 1 Pg. 45-9 (Jan 07 2002) ISSN: 0960-894X [Print] England
• PMID: 11738570 (Publication Type: Journal Article)

Chemical References

• BMS 189664
• Dipeptides
• Fibrinolytic Agents
• Serine Proteinase Inhibitors
• Sulfonamides
• Thrombin

Topics

• Administration, Oral
• Animals
• Binding Sites
• Crystallography, X-Ray
• Dipeptides (administration & dosage, chemistry, pharmacokinetics)
• Disease Models, Animal
• Dogs
• Drug Design
• Drug Evaluation, Preclinical
• Fibrinolytic Agents (administration & dosage, chemistry, pharmacokinetics)
• Humans
• Inhibitory Concentration 50
• Macaca fascicularis
• Mice
• Serine Proteinase Inhibitors (administration & dosage, chemistry, pharmacokinetics)
• Structure-Activity Relationship
• Sulfonamides (administration & dosage, chemistry, pharmacokinetics)
• Thrombin (antagonists & inhibitors)
• Thrombosis (drug therapy, prevention & control)