Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.
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.
Lin
Jian
J
Daiichi Asubio Medical Research Laboratories LLC (DAIAMED), One Kendall Square Building 700, Cambridge, MA 02139, USA. jlin@epixpharma.com
Deng
Hongfeng
H
Jin
Lei
L
Pandey
Pramod
P
Quinn
Jesse
J
Cantin
Susan
S
Rynkiewicz
Michael J
MJ
Gorga
Joan C
JC
Bibbins
Frank
F
Celatka
Cassandra A
CA
Nagafuji
Pamela
P
Bannister
Thomas D
TD
Meyers
Harold V
HV
Babine
Robert E
RE
Hayward
Neil J
NJ
Weaver
David
D
Benjamin
Howard
H
Stassen
Frans
F
Abdel-Meguid
Sherin S
SS
Strickler
James E
JE
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
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D015945:Factor XIa; D013917:Thrombin