Bioorganic & Medicinal Chemistry Letters
Discovery of 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one derivatives as a
new class of ROCK inhibitors for the treatment of glaucoma
a
,
1
b
,
1
b
b
b,
c
b
Yumeng Sun , Yueshan Li , Zhuang Miao , Ruicheng Yang , Yun Zhang , Ming Wu ,
b
a,*
Guifeng Lin , Linli Li
a
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Macular Disease Research Laboratory, Department of Ophthalmology, West China Hospital, Sichuan University, Sichuan 610041, China
b
c
A R T I C L E I N F O
A B S T R A C T
Keywords:
The Rho-associated protein kinases (ROCKs) are associated with the pathology of glaucoma and discovery of
ROCK inhibitors
Structure–activity relationship
Glaucoma
ROCK inhibitors has attracted much attention in recent years. Herein, we report a series of 3,4-dihydrobenzo[f]
[
1,4]oxazepin-5(2H)-one derivatives as a new class of ROCK inhibitors. Structure-activity relationship studies led
to the discovery of compound 12b, which showed potent activities against ROCK I and ROCK II with IC50 values
of 93 nM and 3 nM, respectively. 12b also displayed considerable selectivity for ROCKs. The mean IOP-lowering
effect of 12b in an ocular normotensive model was 34.3%, and no obvious hyperemia was observed. Overall, this
study provides a good starting point for ROCK-targeting drug discovery against glaucoma.
IOP-lowering effect
7
,15,17
Among them, ripasudil18 and
Glaucoma is one of the primary causes of blindness and the global
number of patients with glaucoma is estimated to be more than 111.8
million in 2040.1 Glaucoma patients often bear a combination of
symptoms including elevated intraocular pressure (IOP), irreversible
optic neuropathy and different degrees of corneal endothelial cell
39983, SR-3677, INS117548.
netarsudil,1
9,20
have been approved to use clinically as anti-glaucoma
,2
drugs. Despite a good therapeutic effect, these two drugs show an
adverse effect of conjunctival hyperemia, which could be due to the poor
kinase selectivity.1
,21–24
Therefore, discovering more potent and selec-
3
–5
dysfunction until loss of visual field. Lowing IOP is the most efficient
strategy for the treatment of glaucoma.6 Notably, each millimeter of
mercury (mmHg) reduction in IOP, the risk of the glaucomatous field
impairment progression can be decreased by 10–19% for glaucoma
patients.7
tive ROCK inhibitors is necessary at present.
To identify new ROCK inhibitors, we screened our in-house chemical
library containing about 1000 compounds synthesized by our group,
which led to the retrieving of a ROCK inhibitor with a new scaffold 3,4-
dihydroisoquinolin-1(2H)-one (Hit 1, Fig. 2). Hit 1 is a dual ROCK I/II
Rho-associated protein kinases (ROCKs), which are widely expressed
in the trabecular meshwork (TM), have been demonstrated to play an
inhibitor with IC50 values of 2.062 ± 0.103
μ
M and 0.632 ± 0.059
μ
M,
respectively. A further structural optimization was carried out in this
investigation.
8
important role in the pathology of glaucoma. After activation by Rho-
GTPase, ROCK phosphorylate the intracellular downstream sub-
strates,9 such as myosin phosphatase targeting subunit 1 (MYPT1),
The structural optimization and SAR analyses were focused on three
regions: 3,4-dihydroisoquinolin-1(2H)-one (region I), 1H-indazole (re-
gion II) and anisole (region III).
myosin light chain (MLC), and LIM kinases (LIMK).1
0–13
ROCK inhibitors
have been demonstrated to be able to efficiently decrease IOP by acting
on TM and altering the cytoskeleton.14 Meanwhile, it also plays a role in
In the first step, we fixed region II and III, and varied region I. A total
of four compounds (6, 10a-c) were synthesized. As shown in Scheme 1,
3-methoxybenzylamine reacted with 4-bromo-2-hydroxybenzoyl chlo-
ride (2), which was prepared by refluxing reaction of 4-bromo-2-hydrox-
optic nerve protection through increasing retinal vascular perfusion and
promoting optic nerve regeneration.1
5,16
Currently, a number of ROCK
inhibitors have been reported to anti-glaucoma. Fig. 1 shows several
representative examples, including ripasudil, netarsudil, Y-27632, Y-
ybenzoic acid (1) in SOCl
2
, to generate intermediate 3. Compound 4 was
then obtained by cyclization from intermediate 3. Suzuki-Miyaura
*
These authors contributed equally to this work.
1
Received 5 February 2021; Received in revised form 16 May 2021; Accepted 20 May 2021
Available online 24 May 2021
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