Solid-phase optimisation of achiral amidinobenzyl indoles as potent and selective factor Xa inhibitors.
Starting from the achiral and potent factor Xa inhibitor 1, a new and flexible solid-phase optimisation strategy is described to reduce its cationic character. By replacing one positively charged side chain by a lipophilic substituent, a novel series of highly potent and selective achiral factor Xa inhibitors was discovered. The identified lipophilic replacements in the S4 pocket might be valuable for other approaches towards fXa inhibitors.
Heinelt
U
U
Aventis Pharma, Frankfurt, Germany. uwe.heinelt@aventis.com
Herok
S
S
Matter
H
H
Wildgoose
P
P
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055672:Static Electricity; D013329:Structure-Activity Relationship
D000577:Amides; D065427:Factor Xa Inhibitors; D007211:Indoles; D015842:Serine Proteinase Inhibitors