Discovery of a novel sub-class of ROMK channel inhibitors typified by 5-(2-(4-(2-(4-(1H-Tetrazol-1-yl)phenyl)acetyl)piperazin-1-yl)ethyl)isobenzofuran-1(3H)-one.
A sub-class of distinct small molecule ROMK inhibitors were developed from the original lead 1. Medicinal chemistry endeavors led to novel ROMK inhibitors with good ROMK functional potency and improved hERG selectivity. Two of the described ROMK inhibitors were characterized for the first in vivo proof-of-concept biology studies, and results from an acute rat diuresis model confirmed the hypothesis that ROMK inhibitors represent new mechanism diuretic and natriuretic agents.
Department of Medicinal Chemistry, Rahway, NJ 07065, United States; Department of Ions Channels, Cardiovascular Disease, Rahway, NJ 07065, United States; Department of Drug Metabolism and Pharmacology, Rahway, NJ 07065, United States; Department of Merck Research Laboratories, Rahway, NJ 07065, United States. Electronic address: haifeng_tang@merck.com.
Haifeng
H
Tang
Reynald K
RK
de Jesus
Shawn P
SP
Walsh
Yuping
Y
Zhu
Yan
Y
Yan
Birgit T
BT
Priest
Andrew M
AM
Swensen
Magdalena
M
Alonso-Galicia
John P
JP
Felix
Richard M
RM
Brochu
Timothy
T
Bailey
Brande
B
Thomas-Fowlkes
Xiaoyan
X
Zhou
Lee-Yuh
LY
Pai
Caryn
C
Hampton
Melba
M
Hernandez
Karen
K
Owens
Sophie
S
Roy
Gregory J
GJ
Kaczorowski
Lihu
L
Yang
Maria L
ML
Garcia
Alexander
A
Pasternak
D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D001572:Benzofurans; D051638:Ether-A-Go-Go Potassium Channels; C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D013777:Tetrazoles; C045574:1H-tetrazole
Diuresis; Heart failure; Hypertension; Natriuresis; ROMK