title: Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.
abstract: Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.
authors.affiliation: Daiichi Asubio Medical Research Laboratories LLC (DAIAMED), One Kendall Square Building 700, Cambridge, MA 02139, USA. jlin@epixpharma.com
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Deng
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.forename: Pramod
authors.initials: P
authors.lastname: Pandey
authors.forename: Jesse
authors.initials: J
authors.lastname: Quinn
authors.forename: Susan
authors.initials: S
authors.lastname: Cantin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rynkiewicz
authors.forename: Joan C
authors.initials: JC
authors.lastname: Gorga
authors.forename: Frank
authors.initials: F
authors.lastname: Bibbins
authors.forename: Cassandra A
authors.initials: CA
authors.lastname: Celatka
authors.forename: Pamela
authors.initials: P
authors.lastname: Nagafuji
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bannister
authors.forename: Harold V
authors.initials: HV
authors.lastname: Meyers
authors.forename: Robert E
authors.initials: RE
authors.lastname: Babine
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Hayward
authors.forename: David
authors.initials: D
authors.lastname: Weaver
authors.forename: Howard
authors.initials: H
authors.lastname: Benjamin
authors.forename: Frans
authors.initials: F
authors.lastname: Stassen
authors.forename: Sherin S
authors.initials: SS
authors.lastname: Abdel-Meguid
authors.forename: James E
authors.initials: JE
authors.lastname: Strickler
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D020246:Venous Thrombosis / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D015945:Factor XIa; D013917:Thrombin