ABSTRACT
In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.
Subject(s)
Factor Xa Inhibitors , Prodrugs/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Amidines/chemical synthesis , Amidines/pharmacology , Animals , Biological Availability , Dogs , Drug Design , Prodrugs/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.
Subject(s)
Acrylamides/chemistry , Acrylamides/pharmacokinetics , Antithrombin III/chemical synthesis , Antithrombin III/pharmacokinetics , Factor Xa Inhibitors , Animals , Asparagine/chemistry , Benzamidines/chemistry , Biological Availability , Dogs , Half-Life , Hydrocarbons, Halogenated/chemistry , Inhibitory Concentration 50 , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Prothrombin Time , Rabbits , Rats , Stereoisomerism , Structure-Activity Relationship , Thrombin/antagonists & inhibitors , Trypsin/drug effectsABSTRACT
Substituted acrylamides were used as templates that bridge P1 and P4 binding elements, resulting in a series of potent (sub-nanomolar) and selective factor Xa inhibitors. In this template, cis-geometry of P1 and P4 ligands is highly preferred. SAR on the substituting groups, as well as on modification of P1 and P4 moieties is described. Compounds in this series show good in vivo efficacy in animal models.
