ABSTRACT
A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.
Subject(s)
Anticoagulants/pharmacology , Drug Design , Factor XIa/antagonists & inhibitors , Proline/pharmacology , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Dose-Response Relationship, Drug , Factor XIa/metabolism , Humans , Molecular Structure , Proline/chemical synthesis , Proline/chemistry , Structure-Activity RelationshipABSTRACT
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.
Subject(s)
Indoles/pharmacokinetics , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Administration, Oral , Biological Availability , Humans , Indoles/administration & dosage , Indoles/chemistry , Structure-Activity RelationshipABSTRACT
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
