Design and Optimization of Sulfone Pyrrolidine Sulfonamide Antagonists of Transient Receptor Potential Vanilloid-4 with in Vivo Activity in a Pulmonary Edema Model.

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.

Comparison of the effect of non-ionic and ionic contrast agents on pancreatic histology in a canine model.

CONTEXT: Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography. Controversy exists whether low osmolarity non-ionic contrast agents lessen the rate of pancreatitis and pancreatic injury. To evaluate we used a canine model to compare pancreatography performed with ionic and non-ionic contrast. DESIGN: Dogs were anesthetized and underwent open transduodenal cannulation of the main pancreatic duct under fluoroscopic control until complete acinarization was achieved to maximize injury. Three dogs received diatrozate, an ionic contrast agent with osmolarity of 1,415 mosM and three dogs were injected with omnipaque a non-ionic agent with osmolarity of 672 mosM. MAIN OUTCOME MEASURES: Serial amylase and white cell counts were followed for 48 hours at which time dogs were sacrificed. Each pancreas was then examined for evidence of pancreatitis and cellular injury with both light and electron microscopy. RESULTS: All animals developed significant hyperamylasemia and elevated white blood cell counts, without significant difference in the mean peak amylase (10,721 U/L vs. 9,367 U/L, P=0.876) or white cell counts (25.8 k/mL vs. 24.1 k/mL, P=0.586) between the ionic and non-ionic contrast groups. Light microscopy showed no evidence of pancreatitis in either group of dogs. Electron microscopy showed cellular injury of the ductal cells in two dogs injected with non-ionic contrast. CONCLUSION: In a pancreatic canine model, low osmolarity, non-ionic contrast does not appear to lessen cellular injury.