Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization.
Indole oxoacetic acid derivatives were prepared and evaluated for in vitro binding to and inactivation of human plasminogen activator inhibitor-1 (PAI-1). SAR based on biochemical, physiological, and pharmacokinetic attributes led to identification of tiplaxtinin as the optimal selective PAI-1 inhibitor. Tiplaxtinin exhibited in vivo oral efficacy in two different models of acute arterial thrombosis. The remarkable preclinical safety and metabolic stability profiles of tiplaxtinin led to advancing the compound to clinical trials.
Elokdah
Hassan
H
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. elokdah@wyeth.com
Abou-Gharbia
Magid
M
Hennan
James K
JK
McFarlane
Geraldine
G
Mugford
Cheryl P
CP
Krishnamurthy
Girija
G
Crandall
David L
DL
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002341:Carotid Artery Thrombosis / Q000188:drug therapy; D003328:Coronary Thrombosis / Q000188:drug therapy; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007210:Indoleacetic Acids; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; C488103:tiplaxtinin