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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Pero JE,Matthews JM,Behm DJ,Brnardic EJ,Brooks C,Budzik BW,Costell MH,Donatelli CA,Eisennagel SH,Erhard K,Fischer MC,Holt DA,Jolivette LJ,Li H,Li P,McAtee JJ,McCleland BW,Pendrak I,Posobiec LM,Rivera KLK,Rivero RA

doi

10.1021/acs.jmedchem.8b01344

subject

Has Abstract

pub_date

2018-12-27 00:00:00

pages

11209-11220

issue

24

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

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