ABSTRACT
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Subject(s)
Amides/pharmacology , Bradykinin B1 Receptor Antagonists , Amides/chemistry , Amides/pharmacokinetics , Animals , Biological Availability , Blood-Brain Barrier , Cytochrome P-450 Enzyme Inhibitors , Dogs , Half-Life , Humans , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
