ABSTRACT
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of transient receptor potential vanilloid-4 (TRPV4) cation channels may offer an alternative-and potentially superior-therapy. Efforts directed toward small-molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity, and pharmacokinetic properties are described. Activity of leading exemplars 19 and 27 in an in vivo model suggestive of therapeutic potential is highlighted herein.
Subject(s)
Pulmonary Edema/drug therapy , Pyrrolidines/pharmacology , Sulfonamides/pharmacology , Sulfones/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Humans , Male , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfones/chemistry , Sulfones/pharmacokineticsABSTRACT
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent agonists of the human TGR5 G-protein-coupled receptor is described. Many analogues were readily accessible via solution-phase synthesis which resulted in the rapid identification of key structure-activity relationships (SAR), and the discovery of potent exemplars (up to pEC50=9). Details of the SAR and optimization of this series are presented herein.
Subject(s)
Acrylamides/chemical synthesis , Drug Design , Isoxazoles/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Acrylamides/chemistry , Acrylamides/pharmacology , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.
