Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid‑4 (TRPV4)

A novel
series of pyrrolidine sulfonamide transient receptor potential
vanilloid-4 (TRPV4) antagonists was developed by modification of a
previously reported TRPV4 inhibitor (1). Several core-structure
modifications were identified that improved TRPV4 activity by increasing
structural rigidity and reducing the entropic energy penalty upon
binding to the target protein. The new template was initially discovered
as a minor regio-isomeric side product formed during routine structure–activity
relationship (SAR) studies,
and further optimization resulted in highly potent compounds with
a novel pyrrolidine diol core. Further improvements in potency and
pharmacokinetic properties were achieved through SAR studies on the
sulfonamide substituent to give an optimized lead compound GSK3395879
(52) that demonstrated the ability to inhibit TRPV4-mediated
pulmonary edema in an in vivo rat model. GSK3395879
is a tool for studying the biology of TRPV4 and an advanced lead for
identifying new heart failure medicines.