Investigation of TRPV4 (Transient Receptor Potential Vanilloid 4) ion channel blockers has produced a series of potent pyrrolidine sulfonamides for the potential treatment of pulmonary edema associated with heart failure. <br/>Lead optimization efforts, beginning with a previously reported TRPV4 inhibitor, focused on several core-structure modifications designed to improve TRPV4 activity by increasing structural rigidity and reducing the entropic energy penalty upon binding to the target protein.  A significant breakthrough occurred when a minor regio-isomeric side product was identified which lead to a novel series of pyrrolidine sulfonamides.  Further improvements in potency and pharmacokinetic properties ultimately delivered a pre-clinical candidate.<br/>Efforts to understand various synthetic rearrangements and rationalize emerging SAR will be presented.

Discovery of pyrrolidine sulfonamides as TRPV4 antagonists

2019 Fall National Meeting

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