Discovery of benzimidazole oxazolidinediones as novel and selective nonsteroidal mineralocorticoid receptor antagonists.
Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure-activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Christine
C
Yang
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Jaume
J
Balsells
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Hong D
HD
Chu
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Jason M
JM
Cox
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Alejandro
A
Crespo
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Xiuying
X
Ma
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Lisa
L
Contino
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Patricia
P
Brown
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Sheng
S
Gao
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Beata
B
Zamlynny
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Judyann
J
Wiltsie
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Joseph
J
Clemas
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
JeanMarie
J
Lisnock
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Jack
J
Gibson
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Gaochao
G
Zhou
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Margarita
M
Garcia-Calvo
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Thomas J
TJ
Bateman
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Vincent
V
Tong
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Ling
L
Xu
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Martin
M
Crook
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Peter
P
Sinclair
Merck Research Laboratories, Merck & Co. , Kenilworth, New Jersey 07033, United States.
Hong C
HC
Shen
amide replacement; antagonist; mineralocorticoid receptor; natriuresis effect; oxazolidinedione