Structure-based design of potent, amidine-derived inhibitors of factor Xa: evaluation of selectivity, anticoagulant activity, and antithrombotic activity.
To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.
Wiley
M R
MR
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. wileymr@lilly.com
Weir
L C
LC
Briggs
S
S
Bryan
N A
NA
Buben
J
J
Campbell
C
C
Chirgadze
N Y
NY
Conrad
R C
RC
Craft
T J
TJ
Ficorilli
J V
JV
Franciskovich
J B
JB
Froelich
L L
LL
Gifford-Moore
D S
DS
Goodson
T
T
Herron
D K
DK
Klimkowski
V J
VJ
Kurz
K D
KD
Kyle
J A
JA
Masters
J J
JJ
Ratz
A M
AM
Milot
G
G
Shuman
R T
RT
Smith
T
T
Smith
G F
GF
Tebbe
A L
AL
Tinsley
J M
JM
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy
D000578:Amidines; D000925:Anticoagulants; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D013917:Thrombin; D015951:Factor Xa