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

Abstract

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.

• Authors: Edward J Brnardic, Guosen Ye, Carl Brooks, Carla Donatelli, Linda Barton, Jeff McAtee, Robert M Sanchez, Arthur Shu, Karl Erhard, Lamont Terrell, Grazyna Graczyk-Millbrandt, Yanan He, Melissa H Costell, David J Behm, Theresa Roethke, Patrick Stoy, Dennis A Holt, Brian G Lawhorn
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 21 Pg. 9738-9755 (11 08 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30335378 (Publication Type: Journal Article)

Chemical References

• Pyrrolidines
• Sulfonamides
• TRPV Cation Channels
• pyrrolidine

Topics

• Administration, Oral
• Animals
• Biological Availability
• Drug Design
• Pyrrolidines (chemistry)
• Rats
• Structure-Activity Relationship
• Sulfonamides (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• TRPV Cation Channels (antagonists & inhibitors)