The design of phenylglycine containing benzamidine carboxamides as potent and selective inhibitors of factor Xa

Factor Xa, a critical serine protease in the blood coagulation cascade, has become a target for inhibition as a strategy for the invention of novel anti-thrombotic agents. Here we describe the development of phenylglycine containing benzamidine carboxamides as novel, potent and selective inhibitors of factor Xa. Using PRO_SELECT, a number of highly focused libraries of compounds have been designed and synthesised giving rapid access to a series of potent and selective inhibitors of factor Xa. Key to the potency of these compounds is the lipophilic interaction between phenylglycine residue and the ‘disulphide’ pocket comprising Gln192, Cys191, Cys220 and Gly218.