1. Design and Optimization of Sulfone Pyrrolidine Sulfonamide Antagonists of Transient Receptor Potential Vanilloid-4 with in Vivo Activity in a Pulmonary Edema Model
- Author
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Brian G. Lawhorn, Brian Budzik, Karl F. Erhard, Huijie Li, Carla A. Donatelli, Kalindi Vaidya, Melissa H. Costell, Joseph E. Pero, John J. McAtee, Carl Brooks, Lorraine M. Posobiec, Larry J. Jolivette, Dennis A. Holt, Theresa J. Roethke, Stephen H. Eisennagel, Michael C. Fischer, Matthews Jay M, Arthur Shu, Brent W. Mccleland, Lamont Roscoe Terrell, Sender Matthew Robert, Katrina Rivera, David J. Behm, Israil Pendrak, Ralph A. Rivero, Xiaoping Xu, Edward J. Brnardic, and Peng Li
- Subjects
0301 basic medicine ,TRPV4 ,Male ,Pyrrolidines ,Drug Evaluation, Preclinical ,TRPV Cation Channels ,Pulmonary Edema ,Pharmacology ,01 natural sciences ,Pyrrolidine ,Sulfone ,Rats, Sprague-Dawley ,03 medical and health sciences ,Transient receptor potential channel ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Sulfones ,Receptor ,Sulfonamides ,010405 organic chemistry ,Sulfonamide (medicine) ,Pulmonary edema ,medicine.disease ,0104 chemical sciences ,030104 developmental biology ,chemistry ,Molecular Medicine ,medicine.drug - Abstract
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.
- Published
- 2018