Discovery of SHR0687, a Highly Potent and Peripheral Nervous System-Restricted KOR Agonist

Article abstract of DOI:10.1021/acsmedchemlett.0c00287

Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however, activation

Full text of DOI:10.1021/acsmedchemlett.0c00287

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Letter
Discovery of SHR0687, a Highly Potent and
Peripheral Nervous System-restricted KOR Agonist
Xin Li, Hong Wan, Ping Dong, Bin Wang, Lei Zhang, Qiyue Hu, Ting
Zhang, Jun Feng, Feng He, Chang Bai, Lianshan Zhang, and Weikang Tao
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.0c00287 • Publication Date (Web): 14 Sep 2020
Downloaded from pubs.acs.org on September 15, 2020
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Discovery of SHR0687, a Highly Potent and Peripheral Nervous
System-restricted KOR Agonist
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Xin Li,*,† Hong Wan,† Ping Dong,† Bin Wang,† Lei Zhang,† Qiyue Hu,† Ting Zhang,† Jun Feng,† Feng
He,†¶ Chang Bai,† Lianshan Zhang,‡ Weikang Tao†¶
†Shanghai Hengrui Pharmaceutical CO., LTD., 279 Wenjing Road, Shanghai 200245, China
¶Chengdu Suncadia Medicine CO., LTD., 88 South Keyuan Road, Chengdu, Si Chuan 610000, China
‡Jiangsu Hengrui Medicine CO., LTD., Lianyungang, Jiangsu 222047, China
O
O
H
N
H
N
N
H
N
H
N
O
O
O
N
H
N
H
NH2
SHR0687
KOR EC = 0.53 pM
50
Kpu,u = 0.006
Cl(mL/min/kg)= 10.1 (mouse), 10.5 (rat), 3.1 (dog)
Efficacious dose @ 0.1 mg/kg
ABSTRACT: Analgesics with no abuse liability are highly demanded in the market. KOR agonists have been proved to be strong
analgesics without MOR agonist-related side effects, such as respiratory depression, tolerance, and dependence liability; however,
activation of KOR in the central nervous system (CNS) may cause sedation and anxiety. It has been reported that peripheral KOR
activation produces comparable bioactivity without CNS-related side effects. Herein, we designed and synthesized a novel
tetrapeptide (SHR0687), which was shown to be a highly potent KOR agonist with excellent selectivity over other opioid receptors,
such as MOR and DOR. In addition, SHR0687 displayed favorable PK profiles across species, as well as robust in vivo efficacy in a
rat carrageenan-induced pain model. Notably, SHR0687 exhibited negligible BBB penetration, which was meaningful in
minimizing CNS-related side effects.
KEYWORDS: Opioid receptors, kappa, analgesics, peripheral nervous system, BBB penetration, SHR0687.
agonists have a strong anti-nociceptive effect with minimal
respiratory depression and
Opioid receptors from family A of the G-protein-coupled
receptors include three major subtypes (mu [MOR], kappa
[KOR], and delta [DOR]), which are widely distributed in the
brain, spinal cord, and digestive tract.1,2,3 As well-known
targets for pain treatment, opioid receptors are involved in the
physiologic process of pain-related perception and
modulation.3 In the clinic setting, MOR agonists, such as
morphine, are most widely used powerful analgesics.4
However, activation of MOR often leads to serious side
effects, such as respiratory depression, tolerance, and
dependence liability.5 DOR agonists are less anti-nociceptive
with notable convulsions, which have limited therapeutic
development.6,3 As a potential alternative analgesic, KOR
drug dependence.7 Additionally, KOR agonists have been
shown to be useful for treating pruritus, opiate dependence,
and depression.8
Further research has verified that KOR agonists in the
central nervous system (CNS) may cause sedation and
anxiety,9 whereas peripheral KOR activation produces
comparable bioactivity without CNS-related side effects.10
These inspiring results have spurred considerable interest of
discovering novel KOR agonists with high region selectivity
in the peripheral nervous system (PNS).
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phenethyl amine 4 exhibited high potency by extension of one
3
4
5
6
7
8
9
more carbon chain from compound 2. Further extending the
chain to afford 5 with an EC50= 45 pM satisfied KOR potency.
We preferred to select compound 4 considering it had a less
flexible side chain that might be better for physicochemical
properties. As shown in Table 1, the R2 group with either
morphine or amino acid displayed the same level of potency
(compounds 6 and 4). Inspired by these results, additional
compounds with mono and bis substitutions between the
amide group and phenylpropyl amine linker (7 and 8) were
designed. Unfortunately, the potency dropped completely. It
was speculated that the steric effect close to the amide most
likely affected the binding affinity. As a result, a new strategy
was adjusted to the other side of the N atom close to the
phenyl group. Inserting cyclopropane into the benzyl amine
afforded compound 9 to maintain the potency compared with
6. Thus, more effort was focused on the study of substitution
groups (10-15). It was found that di-substituted group, such as
cyclopropane or di-methyl (10 and 11) were well-tolerated and
the potency was comparable to compound 6. Unexpectedly,
introducing the racemic ethyl substitution improved potency
(compound 12). This result indicated that the less steric group
was more favorable for potency. Subsequently, two mono
methyl with R and S configuration compounds were
investigated. Interestingly, the R group 14 was more potent
than the S configuration 13. Next, the R configuration
isopropyl 15 was shown to decrease potency compared with
14. This result further confirmed the impact of steric effects on
potency. Finally, the tail group R2 was optimized and it was
found that the methyl urea group yielded compound 16 to
exhibit the highest potency in this series.
O
O
O H
H
N
H
N
O
O
N
H
N
H2
N
N
O
O
O H
NH2
N
NH2
Asimadoline
Difelikefalin (CR845)
Figure 1. Structures of asimadoline and difelikefalin (CR845).
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Recently, two peripherally selective KOR agonists were
reported in clinical development at phase III. Asimadoline
(Fig. 1) has been shown to have reasonable efficacy for
treatment of visceral pain.11 Another peptide-based molecule,
difelikefalin (CR845), is undergoing clinical trials for treating
chronic and post-operative pain.12,13 Considering the huge
demand for analgesics without abuse liability, there has been
considerable interest in developing diverse high-potency KOR
agonists without CNS-related side effects. Our program
focuses on the structure-activity relation (SAR) exploration of
peptide oligomers as KOR agonists with high topologic polar
surface areas (TPSAs), which presumably have limited ability
to passively cross the brain-blood barrier (BBB).
Based on previous publications, the N-terminal D-
phenylamine (Phe) functional group of CR-845 is a key
pharmacophore and this area is very sensitive for the binding
activity of KOR.14-16 Herein, we focused on exploring
alternative novel unnatural amino acids to mimic the key Phe
group (Table 1). The initial idea was to introduce cyclized
phenylamine tetrahydroisoquinoline 1, but unfortunately the
potency decreased completely. Then, the open-chained benzyl
amine 2 was shown to have no KOR activity. Subsequently, a
cyclization ring afforded 2,3-dihydro-1H-inden-2-amine 3,
which was still inactive (EC50 > 1000 pM). Interestingly, the
Table 1. Human KOR agonist in vitro activity a
O
O
O
O
H
N
H
N
H
N
H
N
O
R1
N
H
N
H2
N
N
H
R2
O
O
O H
NH2
O
O
key residue
NH2
NH2
Difelikefalin (CR845)
KOR EC50
(pM)
KOR EC50
(pM)
Cpds ID
R1
R2
Cpds ID
R1
R2
N
N
N
H
>1000
>1000
9
O
80
57
1
NH
O
N
N
H
N
CO2
H
2
3
O
10
11
N
H
NH2
N
N
H
N
CO2
H
N
H
O
>1000
78
NH2
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N
N
CO2
H
N
H
4
O
48
12
2.9
NH2
N
H
4
5
6
7
8
N
N
CO2
H
N
H
N
5
6
O
45
54
13
14
15.5
1.4
H
NH2
N
N
CO2
H
CO2H
N
H
9
NH2
NH2
N
H
10
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12
13
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N
N
CO2
H
CO2H
N
H
7
>1000
15
9.5
NH2
NH2
N
H
N
O
N
CO2
H
N
H
8
>1000
16
0.53
N
H
N
H
NH2
N
H
a EC50 values are mean of two or more runs with CR845 as positive control for each batch (CR845 KOR EC50 = 2.62 ± 0.75 pM, n
= 5).
This optimized pharmacophore residue was also supported
Figure 2. The modeled binding pose of compound 16 with
by computational docking studies. Based on the overlay of the
agonist-bound KOR protein structure (PDB code: 6B73) and
the 3D-bound ligand conformation of the tetrapeptide agonist
(DIPP-NH2) in DOR co-Xray crystal structure (PDB code:
4RWA), we modeled the bound conformation of compound 16
to KOR, as depicted in Figure 2. The basic nitrogen in the
phenethyl amine group makes strong salt bridge interaction
with ASP138 and hydrogen bond with TYR320. The phenyl
group of phenethyl amine is enclosed by three aromatic and
hydrophobic side chains of HIS291, TYR139, and ILE294.
This pocket helped the gain of potency of R isomer 14
compare with compound 13 might due to a more favorable
binding position. The peptidic backbone amide groups make
hydrogen bonds with ASP138, GLN115, and TYR312,
respectively. The lysine group of compound 16 is within the
salt bridge distance to GLU209, while the tail urea motif is
largely exposed towards the solvent. Additionally, the methyl
urea group seemed to make two interactions in the binding
pocket of KOR. One is intramolecular hydrogen bond with
lysine NH, and the other is dipole interaction with Arg202.
These two interactions possibly enhanced the potency.
agonist bound KOR protein structure.
As an interesting result, compound 16 (SHR0687) was
selected for further in vitro and in vivo evaluations. As shown
in Table 2, this tetrapeptide displayed excellent selectivity
over other opioid receptors, such as MOR and DOR, whose
EC50 was > 50000 nM in cAMP accumulation assays.
Table 2. In vitro potency of SHR0687 a
Compound ID
MW / AlogP / PSA
hKOR EC50 (pM)
hMOR EC50 (nM)
hDOR EC50 (nM)
SHR0687
720.9 /2.06 /186.8
0.53
>50000
>50000
a
The positive control for hMOR and hDOR test was
Morphine (hMOR EC50 = 79.12 ± 9.91 nM, n = 3; hDOR EC50
= 203.97 ± 33.51 nM, n = 3).
In addition, SHR0687 was stable in in vitro liver
microsomes across species, such as rats, mice, dogs, and
humans (Table 3), which correlated well with the in vivo PK
results (Table 5). Moreover, the cytochrome P450 inhibition of
SHR0687 was investigated to assess the potential likelihood of
drug−drug interactions (DDIs) with major CYP isoforms,
including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and
CYP3A4. SHR0687 was found with no obvious CYP450
inhibition with all CYP isoform IC50 values >30 μM. The
hERG IC50 of SHR0687 was > 30 μM, indicating a higher
cardiac safety margin.
Table 3. LMS, CYP, and hERG data of SHR0687
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displayed remarkable efficacious characteristics, even at a 0.03
Compound ID
LMS t1/2 (min)a
SHR0687
mg/kg dosage. A clear dose-dependent effect was observed
from 0.03-0.3 mg/kg (28.9%-66.7%; Fig. 3). It is worth
mentioning that SHR0687 exhibited comparable or slightly
better efficacy at the same dosage (66.7% vs. 61.9% @ 0.3
mg/kg) with CR-845 employed as a control group in the same
study.
40 (h); >268 (r); 115
(m); 216 (d)
hCYPs IC50 (μM)
1A2/2C9/2D6/3A4(m)a/3A4(t)c2C19
All >30
9
hERG IC50 (patchliner, μM)
>30
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b
ah = humans, r = rats, m = mice, d = dogs; m: midazolam; ct:
testosterone (FDA recommended 3A4 substrates)
Considering that our goal was discovery of a KOR agonist
with good PNS selectivity and avoiding CNS side effects, we
investigated the brain permeability of SHR0687 in a rat BBB
model using the Kpu,u value for evaluation of CNS
penetration.17,18 As summarized in Table 4, the Kpu,u value of
SHR0687 was 0.006, suggesting that the BBB penetration
capacity of SHR0687 was very limited.
Table 4. BBB penetration data of SHR0687 on SD rat (iv, 1
mg/kg)
Figure 3. Efficacy study of SHR0687 on a rat carrageenan-
induced pain model. N=8 rats in each group. Statistical
comparisons were performed using the Excel software t-test. The
data between the model and control groups were analyzed and
compared to determine whether there was a significant statistical
significance. *P <0.05 indicates that there is a significant
difference between the model and control groups, ** P <0.01
indicates that there is a highly significant difference between the
model and control groups, #P<0.05 indicates that there is a
significant difference between the model and control groups, ##P
<0.01 indicates that there is a highly significant difference
between the model and the administration groups.
Brain
fu_rat
fu_brain plasma
Cmpd
tissue
(ng/g)
Kpu, u
plasma
tissue
(ng/ml)
SHR0687
21.1%
2.58%
1144
57.2
0.006*
*T-test (P=0.007)
As summarized in Table 5, SHR0687 has a favorable PK
profile across species with low clearance and good in vivo
exposure (AUC=1656 ng/mL*h on mice; AUC=1553
ng/mL*h on rats; AUC=2619 ng/mL*h on dogs). The
adequate exposure was helpful for the following rat in vivo
pain model study at a relatively lower dosage.
The synthesis of SHR0687 was straightforward, as shown in
scheme 1. Our strategy was to synthesize N and C terminal
scaffolds in parallel, then couple two pieces at the late stage.
The N terminal scaffold of methyl urea intermediate 20 was
prepared in four steps. Initially, commercially available
primary amine 17 was treated with methylcarbamic chloride,
followed by deprotection of Boc group to afford urea substrate
18. Then, 18 was coupled with carboxylic acid 19, followed
by removal of the Fmoc protecting group to achieve N
terminal substrate 20 in a decent yield. The C terminal
scaffold synthesis began with known intermediate 21 (see
supporting information). Treating intermediate 21 with
chloroacetyl chloride yielded compound 22, which was
coupled by (R)-2-phenylpropan-1-amine 23, then followed by
Boc protection. Subsequently the benzyl ether group was
removed via hydrogenation afforded carboxylic acid 24 in an
overall yield of 82% for four steps. The last two steps were
coupling intermediates 24 and 20, followed by removal of the
Boc group, with successful production of compound 16
(SHR0687).
Table 5. Intravenous PK data of SHR0687 a,b
Species
Mouse
1656
Rat
Dog
AUC0-t (ng/mL*h)
1553
2619
t1/2(h)
0.34
10.1
297
4.78
10.5
4515
4.45
3.1
CL (mL/min/kg)
Vz (mL/Kg)
1236
aCL is clearance; t1/2 is the half-life of the compound exposure
in plasma; AUC is the area under the curve. bThe dosage for
mouse and rat was 1 mg/kg and for dog was 0.5 mg/kg.
Furthermore, SHR0687 was investigated in
carrageenan-induced pain model to evaluate the therapeutic
effect.19 In agreement with the high in vitro potency, SHR0687
a
rat
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Scheme 1. Synthetic route of SHR0687
4
5
6
O
H
Boc
N
H2N
a, b
c, d
OH
N
O
N
O
Boc
NH2
N
N
N
H
HN
Fmoc
H
H
H
HN
N
19
23
NH2
7
8
O
HN
Boc
20
17
18
9
O
O
O
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
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e
f,g,h
H2N
O
N
O
N
OH
i
N
H
Bn
Cl
N
Bn
N
N
H
H
O
O
O
Boc
O
O
21
22
24
O
O
O
O
H
H
H
N
H
N
N
N
j
N
H
N
N
O
N
N
H
N
O
H
Boc
O
O
O
O
N
H
N
N
N
H
H
H
NH2
HN
Boc
25
16
(SHR0687)
Reagents and conditions: (a) methylcarbamic chloride, DIPEA, DCM, r.t. 2h (b) HCl/Dioxane, DCM, r.t. 2h (c) 19, HATU, Et3N, DMF,
r.t. 4h (d) Et3N, DMF, r.t. 12h, 32% four steps (e) 2-chloroacetyl chloride, Et3N, DCM, r.t. 12h (f) 23, KI, K2CO3, DMF, 60°C 12h (g)
(Boc)2O, Et3N, DCM, r.t. 12h (h) Pd/C, H2, MeOH, r.t. 12h, 82% four steps (i) 20, HATU, Et3N, DMF, r.t. 12h (j) HCl/Dioxane, DCM, r.t.
12h, 50% two steps.
In summary, SHR0687 exhibited a highly potent KOR
agonist with excellent selectivity over other opioid receptors,
such as MOR and DOR. This novel tetrapeptide displayed
favorable PK profiles across species, as well as robust in vivo
efficacy in a rat carrageenan-induced pain model. Notably,
SHR0687 showed minimal BBB penetration with an
extremely low Kpu,u value, thus indicating marginal CNS-
related side effects for the potential therapeutic treatment of
pain.
ABBREVIATIONS
MOR, mu-opioid receptor; KOR, kappa-opioid receptor;
DOR, delta-opioid receptor; PNS, peripheral nervous system;
CNS, central-nervous system; BBB, blood-brain barrier; DCM,
dichloromethane; hERG, human ether-a-go-go related gene;
CYP, cytochrome P450 enzymes; PK, pharmacokinetics;
HATU,2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-
tetramethyluronium hexafluorophosphate; Boc, t-Butyloxy
carbonyl; DIPEA, N,N-Diisopropylethylamine.
REFERENCES
ASSOCIATED CONTENT
Supporting Information
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Synthetic procedures, analytical data, in vitro assay protocols, in
vivo pharmacokinetic studies, and in vivo efficacy model details
are available free of charge on the ACS publications website.
AUTHOR INFORMATION
Corresponding Author
* lix@shhrp.com
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ACKNOWLEDGMENT
We thank Guimei Yang, Tao Liu, Dongdong Bai, Zhendong Xue,
Yuchang Mao, Lilin Liu, Anle Zhang, Wenjian Qian and the
entire KOR project team for their contributions.
8. Kumagai, H.; Ebata, T.; Takamori, K.; Miyasato, K.;
Muramatsu, T.; Nakamoto, H.; Kurihara, M.; Yanagita, T.; Suzuki, H.
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