Design and Optimization of Sulfone Pyrrolidine Sulfonamide Antagonists of Transient Receptor Potential Vanilloid‑4 with in Vivo Activity in a Pulmonary Edema Model

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.