N(2)-Aroylanthranilamide inhibitors of human factor Xa.
Reversal of the A-ring amide link in 1,2-dibenzamidobenzene 1 (fXa K(ass) = 0.81 x 10(6) L/mol) led to a series of human factor Xa (hfXa) inhibitors based on N(2)-aroylanthranilamide 4. Expansion of the SAR around 4 showed that only small planar substituents could be accommodated in the A-ring for binding to the S1 site of hfXa. Bulky groups such as 4-isopropyl, 4-tert-butyl, and 4-dimethylamino were favored in the B-ring to interact with the S4 site of hfXa. The central (C) ring containing a 5-methanesulfonamido group yielded greater activity than carbamoyl groups. Combining the beneficial features from the B- and C-ring SAR, compound 55 represents the most potent hfXa inhibitor in the N(2)-aroylanthranilamide 4 series with hfXa K(ass) = 58 x 10(6) L/mol (K(i) = 11.5 nM).
Yee
Y K
YK
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285, USA.
Tebbe
A L
AL
Linebarger
J H
JH
Beight
D W
DW
Craft
T J
TJ
Gifford-Moore
D
D
Goodson
T
T
Herron
D K
DK
Klimkowski
V J
VJ
Kyle
J A
JA
Sawyer
J S
JS
Smith
G F
GF
Tinsley
J M
JM
Towner
R D
RD
Weir
L
L
Wiley
M R
MR
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
C406227:2-(4-(dimethylamino)benzoylamino)-5-methanesulfonylamino-N'-(4-methoxyphenyl)benzamide; D000925:Anticoagulants; D001549:Benzamides; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D013449:Sulfonamides; D015951:Factor Xa