title: Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. elokdah@wyeth.com
authors.forename: Hassan
authors.initials: H
authors.lastname: Elokdah
authors.forename: Magid
authors.initials: M
authors.lastname: Abou-Gharbia
authors.forename: James K
authors.initials: JK
authors.lastname: Hennan
authors.forename: Geraldine
authors.initials: G
authors.lastname: McFarlane
authors.forename: Cheryl P
authors.initials: CP
authors.lastname: Mugford
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: David L
authors.initials: DL
authors.lastname: Crandall
mesh_terms: 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
chemical_list: D007210:Indoleacetic Acids; D007211:Indoles; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; C488103:tiplaxtinin