Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Scott B
SB
Hoyt
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Whitney
W
Petrilli
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Clare
C
London
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Gui-Bai
GB
Liang
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Jim
J
Tata
Department of Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrücken, Germany.
Qingzhong
Q
Hu
Department of Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrücken, Germany ; ElexoPharm GmbH , Im Stadtwald, D-66123 Saarbrücken, Germany.
Lina
L
Yin
ElexoPharm GmbH , Im Stadtwald, D-66123 Saarbrücken, Germany.
Chris J
CJ
van Koppen
Department of Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Campus C2-3, D-66123 Saarbrücken, Germany.
Rolf W
RW
Hartmann
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Mary
M
Struthers
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Tom
T
Wisniewski
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Ning
N
Ren
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Charlene
C
Bopp
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Andrea
A
Sok
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Tian-Quan
TQ
Cai
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Sloan
S
Stribling
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Lee-Yuh
LY
Pai
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Xiuying
X
Ma
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Joe
J
Metzger
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Andreas
A
Verras
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Daniel
D
McMasters
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Qing
Q
Chen
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Elaine
E
Tung
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Wei
W
Tang
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Gino
G
Salituro
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Nicole
N
Buist
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Joe
J
Clemas
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Gaochao
G
Zhou
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Jack
J
Gibson
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Carrie Ann
CA
Maxwell
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Mike
M
Lassman
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Theresa
T
McLaughlin
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Jose
J
Castro-Perez
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Daphne
D
Szeto
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Gail
G
Forrest
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Richard
R
Hajdu
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Mark
M
Rosenbach
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
Yusheng
Y
Xiong
Aldosterone synthase; CYP11B2; hit-to-lead; hypertension