Design and synthesis of potent and selective 5,6-fused heterocyclic thrombin inhibitors.
Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.
Dominguez
C
C
DuPont Pharmaceuticals Company, Wilmington, DE 19880-0500, USA.
Duffy
D E
DE
Han
Q
Q
Alexander
R S
RS
Galemmo
R A
RA
Park
J M
JM
Wong
P C
PC
Amparo
E C
EC
Knabb
R M
RM
Luettgen
J
J
Wexler
R R
RR
D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats
D000578:Amidines; D000991:Antithrombins; D006571:Heterocyclic Compounds; D007211:Indoles; C119484:XU 817