Generation of potent coagulation protease inhibitors utilizing zinc-mediated chelation.
Inhibition of coagulation proteases such as thrombin, fXa, and fVIIa has been a focus of ongoing research to produce safe and effective antithrombotic agents. Herein, we describe a unique zinc-mediated chelation strategy to streamline the discovery of potent inhibitors of fIIa, fXa, and fVIIa. SAR studies that led to the development of selective inhibitors of fXa will also be detailed.
Young
Wendy B
WB
Celera, 180 Kimball Way, South San Francisco, CA 94080, USA. Wendy.Young@Celera.com
Sprengeler
Paul
P
Shrader
William D
WD
Li
Yong
Y
Rai
Roopa
R
Verner
Erik
E
Jenkins
Thomas
T
Fatheree
Paul
P
Kolesnikov
Aleksandr
A
Janc
James W
JW
Cregar
Lynne
L
Elrod
Kyle
K
Katz
Brad
B
D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D002614:Chelating Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005167:Factor VII / Q000037:antagonists & inhibitors; D065427:Factor Xa Inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D015032:Zinc / Q000737:chemistry*
D000925:Anticoagulants; D002614:Chelating Agents; D065427:Factor Xa Inhibitors; D011480:Protease Inhibitors; D005167:Factor VII; D013917:Thrombin; D015032:Zinc