Sulfonamidopyrrolidinone factor Xa inhibitors: potency and selectivity enhancements via P-1 and P-4 optimization.
Sulfonamidopyrrolidinones were previously disclosed as a selective class of factor Xa (fXa) inhibitors, culminating in the identification of RPR120844 as a potent member with efficacy in vivo. Recognizing the usefulness of the central pyrrolidinone template for the presentation of ligands to the S-1 and S-4 subsites of fXa, studies to optimize the P-1 and P-4 groups were initiated. Sulfonamidopyrrolidinones containing 4-hydroxy- and 4-aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination with 4-hydroxybenzamidine. Compound 20b (RPR130737) was shown to be a potent fXa inhibitor (K(i) = 2 nM) with selectivity against structurally related serine proteinases (>1000 times). Preliminary biological evaluation demonstrates the effectiveness of this inhibitor in common assays of thrombosis in vitro (e.g. activated partial thromboplastin time) and in vivo (e.g. rat FeCl(2)-induced carotid artery thrombosis model).
Choi-Sledeski
Y M
YM
Departments of Cardiovascular Drug Discovery and New Leads Generation, Rhône-Poulenc Rorer, 500 Arcola Road, Collegeville, Pennsylvania 19426-0107, USA.
McGarry
D G
DG
Green
D M
DM
Mason
H J
HJ
Becker
M R
MR
Davis
R S
RS
Ewing
W R
WR
Dankulich
W P
WP
Manetta
V E
VE
Morris
R L
RL
Spada
A P
AP
Cheney
D L
DL
Brown
K D
KD
Colussi
D J
DJ
Chu
V
V
Heran
C L
CL
Morgan
S R
SR
Bentley
R G
RG
Leadley
R J
RJ
Maignan
S
S
Guilloteau
J P
JP
Dunwiddie
C T
CT
Pauls
H W
HW
D000578:Amidines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy
D000578:Amidines; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011760:Pyrrolidinones; C121695:RPR 130737; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D013450:Sulfones