TRPV4 is a ligand-gated Na+/Ca2+ ion channel that is highly expressed in the pulmonary vasculature and its activation is believed to cause the debilitating pulmonary edema associated with heart failure. We identified the pyrrolidine sulfonamide 1 as a promising pre-candidate but were unable to progress the compound into a rat safety assessment study due to its poor oral bioavailability (7%) from high dose crystalline solid. Therefore, we implemented two strategic approaches to overcome the poor suspension dose oral exposure, both of which were aimed at improving aqueous solubility by introducing basic amines. A glycinate prodrug (2) provided excellent exposure of the parent when orally administered at both low and high doses in the rat and dog. We also converted the diol to the corresponding amino-alcohol, taking advantage of the reduced lipophilicity of 1 that was necessary to mitigate selectivity concerns (hERG and phospholipidosis) that had been identified in earlier, more lipophilic amino-alcohol analogs. This led to the identification of 3, a TRPV4 antagonist development candidate.

Highly soluble TRPV4 antagonists for oral and IV delivery

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.