Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ

Article abstract of DOI:10.1016/j.bmcl.2020.126955

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

Full text of DOI:10.1016/j.bmcl.2020.126955

Journal Pre-proofs
Discovery and SAR of Aryl Hydroxy Pyrimidinones as Potent Small Molecule
Agonists of the GPCR APJ
Michael C. Myers, Donna M. Bilder, Cullen L. Cavallaro, Hannguang J. Chao,
Shun Su, Neil T. Burford, Akbar Nayeem, Tao Wang, Mujing Yan, Robert A.
Langish, Marta Dabros, Yi-Xin Li, Anne V. Rose, Kamelia Behnia, Joelle M.
Onorato, Peter S. Gargalovic, Ruth R. Wexler, R. Michael Lawrence
PII:
S0960-894X(20)30008-1
DOI:
https://doi.org/10.1016/j.bmcl.2020.126955
BMCL 126955
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Accepted Date:
15 November 2019
1 January 2020
Please cite this article as: Myers, M.C., Bilder, D.M., Cavallaro, C.L., Chao, H.J., Su, S., Burford, N.T., Nayeem,
A., Wang, T., Yan, M., Langish, R.A., Dabros, M., Li, Y-X., Rose, A.V., Behnia, K., Onorato, J.M., Gargalovic,
P.S., Wexler, R.R., Michael Lawrence, R., Discovery and SAR of Aryl Hydroxy Pyrimidinones as Potent Small
Molecule Agonists of the GPCR APJ, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/
10.1016/j.bmcl.2020.126955
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Discovery and SAR of Aryl Hydroxy
Pyrimidinones as Potent Small Molecule
Agonists of the GPCR APJ
Leave this area blank for abstract info.
Michael C. Myers,* Donna M. Bilder, Cullen L. Cavallaro, Hannguang J. Chao, Shun Su, Neil T. Burford,
Akbar Nayeem, Tao Wang, Mujing Yan, Robert A. Langish, Marta Dabros, Yi-Xin Li, Anne V. Rose, Kamelia
Behnia, Joelle M. Onorato, Peter S. Gargalovic, Ruth R. Wexler, and R. Michael Lawrence
O
N
H3C
APJ/HEK293
N
OH
3 (100%)
cAMP EC50 (nM)
H3CO
CH3
30

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery and SAR of Aryl Hydroxy Pyrimidinones as Potent Small Molecule
Agonists of the GPCR APJ
Michael C. Myers,* Donna M. Bilder, Cullen L. Cavallaro, Hannguang J. Chao, Shun Su, Neil T. Burford,
Akbar Nayeem, Tao Wang, Mujing Yan, Robert A. Langish, Marta Dabros, Yi-Xin Li, Anne V. Rose,
Kamelia Behnia, Joelle M. Onorato, Peter S. Gargalovic, Ruth R. Wexler, and R. Michael Lawrence
Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry
efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor
whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function
of heart failure patients. A high throughput screen was undertaken to identify small molecule hits
that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight
aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and
medicinal chemistry efforts to improve its properties.
Keywords:
Agonist
APJ
2009 Elsevier Ltd. All rights reserved.
Atropisomer
GPCR
Heart Failure
molecule18-26 agonists of APJ. The medicinal chemistry goals for
our work on this target were to discover, validate, and optimize a
1. Introduction
Heart failure (HF) occurs when the heart muscle can no longer
provide the body with an adequate blood supply and represents a
serious disease of unmet medical need for patients. Greater than 5
million people are currently living with HF in the United States,
and this population is expected to grow as the mean population age
increases.1 One million people will be hospitalized this year due
to HF, resulting in both societal and economic burdens for both
families and government health care systems. New medicines that
seek to relieve symptoms, reduce hospitalization rates, improve
the quality of life and extend life represent significant ongoing
efforts in pharmaceutical research.2,3
small molecule agonist of the APJ receptor that could mimic the
effects of the endogenous ligand (pyr1)apelin-13.
To meet the first goal, a high-throughput screen (HTS) was
developed based on the ability of (pyr1)apelin-13 to signal though
the G-protein (Gi) to inhibit forskolin stimulated cAMP
production in a HEK293 cell line (APJ agonism).5,27 The HTS was
run on the BMS screening deck at a 10 M single point
concentration. Compounds that displayed >20% inhibition of
forskolin stimulated cAMP (Ymax) and <20% efficacy against a
parental HEK293 cell line lacking the APJ receptor were selected.
As part of the screening triage process, confirmed hits were
counter-screened against the AT1 receptor. Any cross-activity
with the AT1 receptor was important to characterize given that the
AT1 receptor is the closest homologue to the APJ receptor.4 This
triage process lead to the discovery of two weakly active small
molecule aryl hydroxy pyrimidinone (AHP) agonists, 1 and 2
(Figure 1), that were intriguing due to their low molecular weights
and full agonist responses.
The APJ receptor4 was deorphanized in 1998 with the
identification of a peptide (apelin) as the endogenous agonist.5
The linear apelin peptide exists as a 77 amino acid preproprotein.
This peptide is proteolytically truncated to shorter active variants,
the major contributor of which is a 13-mer peptide known as
pyroglutamated apelin-13 (pyr1)apelin-13. In recent clinical
studies, (pyr1)apelin-13 demonstrated improvements in cardiac
performance.6-8 Newby and co-workers have shown that agonism
of the apelin/APJ system provides beneficial hemodynamic
effects, including cardiac output and ejection fraction increases
without significant change in blood pressure or heart rate.9-11
Significant progress has been made in recent years by several
groups working to design peptido-mimetic12-17 and small

O
N
N
O
N
APJ/HEK293
cAMP EC50 (nM)
MW = 262 g/mol
H3C
5000 (100%)
S
OH
N
Table
H3C
1. N-1
1
S
OH
(N-1)
R1
O
N
CH3
N
hAPJ EC50 (nM)a
APJ/HEK293
cAMP EC50 (nM)
MW = 240 g/mol
cmpd
R1
H3C
4400 (100%)
0.07 (100%)
S
OH
H
1
3
4
5
6
7
8
9
10
11
12
13
14
5000  4800
64  90
940  650
6800  2200
100  50
2900  1200
2600  110
250  140
160  55
155  10
90  60
140  34
100  90
2
2-OCH3
3-OCH3
4-OCH3
2-CH3
3-CH3
4-CH3
2-Cl
CH2
APJ/HEK293
pyrGluRPRLSHKGPMPF
(pyr1)apelin-13
cAMP EC50 (nM)
2-F
2-Br
2-CF3
Figure 1. Structures and potencies of aryl hydroxy pyrimidinone HTS Hits, 1
and 2 vs. (pyr1)apelin-13.
2-CH2CH3
2-OCH2CH3
aData represent the mean SEM, n = 2 or more determinations
substituted phenyl SAR of the AHP core.
Though weakly active, these hits represented excellent small
molecule starting points to initiate a SAR campaign. Optimization
efforts on the AHP chemotype began by utilizing library synthesis
to explore SAR at the N-1 position of the AHP core. A 2-step/1-
NH2
O
O
Br
S
NH
+
H3C
HO
OH
+
R1
step i.
step ii.
O
N
i. DMF, 50 oC, 6 h
N
H3C
ii. cool to 40 oC,
HATU, DIEA, 18 h
20-45% yields
S
OH
(N-1)
R1
pot synthetic route was developed that utilized commercially
available thiourea starting materials (Scheme 1).
Scheme 1. Synthesis of sulfur sidechain AHP analogs.
To produce AHP analogs using this synthetic route, substituted
phenyl thioureas were alkylated with 1-bromo propane.
Condensation of the subsequent S-alkylated intermediate (not
shown) with malonic acid28 in
a
HATU facilitated
coupling/cyclization reaction sequence produced a variety of
substituted phenyl AHP analogs. As part of this work, variations
at the N-1 position with acyclic groups were also explored, but it
was found that substituted phenyl analogs provided significantly
better activity (Table 1).
The data from this work showed that ortho substitution on the
phenyl ring provided analogs with nearly 50-fold potency
increases relative to phenyl analog 1. The 2-methoxy phenyl
analog 3, displayed full APJ agonism with an EC50 of 60 nM in
the HEK293 cell line. The 3-methoxy phenyl analog 4 and 4-
methoxy phenyl analog 5 displayed a 16-fold and 113-fold potency
decrease, respectively, compared to analog 3. A similar trend was
noted for the methyl substituted analogs were meta analog 7 and
para analog 8 were less potent than ortho methyl analog 6.
Electron withdrawing and donating groups (10-14) were tolerated
at the ortho position with only minor changes in potency relative
to analog 3. Importantly, all analogs displayed activations (Ymax)
consistent with full agonism observed with (pyr1)apelin-13.

NH
NH
To explore further peripheral groups on this chemotype,
H3C
CN
H3C
AlMe3, toluene
O
+
R1
R3
H3CO
NH2
100 oC, 2 h
30-38%
N
H3CO
R1
R2
S
N
OH
H3CO
O
R3
diethyl malonate
N
with or without -substitution
H3C
NaH, nBuOH
cmpd
R2
R3
hAPJ EC50 (nM)a
N
OH
R1
H3CO
90 oC, 20 h
3
15
16
17
18
19
20
21
22
H
H
H
H
64  90
23  4
78  35
200  90
1400  840
860  230
1700  70
340  74
570  160
propyl
isopropyl
isobutyl
butyl
45-77% yields
methyl
ethyl
butyl
benzyl
allyl
isopropyl 450  230
H
H
propyl
propyl
propyl
propyl
propyl
propyl
propyl
propyl
Modification of the thioether sidechain (R2) showed that
various alkyl groups were equally preferred (compounds 3, 15,
16). Substitution off the malonic acid derived carbon (R3) resulted
in analogs (18-23) with a decrease in potency relative to
compounds substituted with an H at R3 .
23
S-24
R-25
40  34
160  65
aData represent the mean  SEM, n = 2 or more determinations.
different sidechains (R2) and -substitution (R3) on the malonic
acid component were introduced while maintaining a 2-methoxy
phenyl ring at the N-1 position of the AHP ring (Table 2)
employing the same chemistry as shown in Scheme 1.
The presence of ortho substituents on adjoining planar rings
can lead to atropisomers.29
Chiral super critical fluid
chromatography (SFC) was employed to establish if atropisomers
were observed and to identify conditions to separate stable
atropisomers from the presumed racemic mixture. Conditions
were identified that lead to baseline separation of the two
atropisomers of 2-methoxyphenyl analog 3, S-24 and R-25 (Table
2). The single atropisomers S-24 and R-25 were found to be stable
o
to isomerization for 24 hours at 60 C in DMSO. The absolute
configurations of S-24 and R-25 were confirmed by single crystal
X-ray diffraction analysis of each individual atropisomer.30,31 The
dihedral angle of the 6,6-ring system was nearly perpendicular at
82o in the crystalline form. The S-isomer (S-24) was found to be
more active than the R-isomer (R-25) by a factor of four.
While the in vitro biotransformation work on compound 3 did
not show oxidation or displacement of the sulfur, replacing the
sulfur with a carbon linkage would generate analogs that would
have less potential for in vivo metabolic activation. Aliphatic
sidechain AHP analogs were synthesized from commercially
available 2-methoxy aniline derivatives and valeronitrile via a
similar addition/cyclization sequence32 utilized for the sulfur
sidechain analogs (Scheme 2).
Table 2. Sidechain and malonic acid substitution SAR of the AHP core.
Scheme 2. Synthesis of aliphatic sidechain AHP analogs.
These analogs where then assayed to compare their potencies
relative to sulfur sidechain AHP analog 3 (Table 3).

3 nM and 2 nM, respectively. When progressing compounds
through SAR that exist as a mixture of atropisomers, it is common
to try to remove the C2 axis of chirality so that analogs no longer
require late stage chiral purification.29 Installation of a 2,6-
dimethoxyphenyl ring at the N-1 position of the AHP core was
achieved with compound 32. Importantly the achiral analog 32
maintained good potency relative to racemic 29. The combination
of a substituted malonic acid component (4-methoxy-benzyl) with
the N-1 2,6-dimethoxyphenyl ring resulted in a potent hybrid
analog 33, that suggested further modification at this position
would be tolerated for potency.
Table 3. AHP analogs containing an aliphatic sidechain.
During investigations of AHP compounds like 3 and 26,
instability was observed in PBS solutions that were used for
preparing in vivo dosing samples.30 For example, after 8 hours, 1
week and 2 weeks at room temperature as a PBS buffer solution,
compound 28 was found to have decreasing purities of 92%, 57%
and 48%, respectively. It was observed that for unstable analogs,
a ring-opened degradant was identified as a major component30,
albeit with less potency relative to the parent molecules. The
medicinal chemistry focus shifted quickly toward identifying AHP
analogs that were stable in PBS solution. Interestingly, analogs
that contain 2,6-disubstitution on the lower phenyl ring were found
O
R3
N
H3C
X
N
OH
R1
H3CO
The direct sulfur vs. carbon analog comparison demonstrated
that the carbon analog 26 had modestly improved potency
compared to the sulfur analog 3. Compound 26 was also found to
exist as a mixture of atropisomers, like the sulfur sidechain analog
3. Chiral SFC separation allowed for the isolation of single
cmpd
X
R1
R3
hAPJ EC50 (nM)a
3b
H
64  90
22  36
24  16
31  40
5  4
3  1
2  1
S
H
H
H
H
26b
27c
28d
29b
30c
31d
32e
33e
H
H
H
H
H
H
H
O
O
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
3
30
N
N
H3C
H3C
S
N
OH
N
OH
methyl
methyl
methyl
methoxy
methoxy
H3CO
H3CO
CH3
11  10
4-OCH3-Bn 13  3
91, 96, 94
95, 82, 95
Metabolic stability
HRM (% remaining)
aData represent the mean  SEM, n = 2 or more determinations.
bracemic mixture of atropisomers. cfast eluting single
atropisomer. dslow eluting single atropisomer. eC2-symmetric
achiral molecule.
>20 uM
230, 12
>20 uM
131, 10
CYP inhibition (IC50
)
PAMPA
(pH 5.5, 7.4; nm/sec)
>50 uM
>80 uM
>14 uM
>80 uM
PXR(EC50
)
)
to be stable in PBS solution after exposure up to 2 weeks with no
measurable degradation.
hERG flux (IC50
Compounds 3 and 30 were selected for study in selectivity
assays and mouse PK (Figure 2).30 Metabolic stability for 3 and 30
were excellent and the compounds showed good off target liability
profiles versus CYP, PXR, and hERG. Importantly, mouse PK (10
mg/kg; PO) was acceptable for both analogs and established
compounds 3 and 30 as potential in vivo tool molecules.
4400 nM
4 h
Cmax
Tmax
1680 nM
4 h
mouse PK
(10 mg/kg; PO)
29000 nM*h
AUCtotal
10200 nM*h
atropisomers 27 and 28.30 Exchanging the sulfur of the AHP side
chain with a smaller carbon atom did not alter the atropisomer
stability profile of the series. The fast eluting isomer 27 was nearly
equipotent with the slow eluting isomer 28.
The increased potency seen with ortho phenyl substitution
strongly suggested that the bioactive conformation is one where
the phenyl ring is orthogonal to the AHP core. Further
stabilization of this apparent bioactive conformation could be
achieved by adding a C6 substituent.
Figure 2. Profiling and PK data of AHP compounds 3 and 30.
This hypothesis was supported when 2,6-disubstitution on the
N-1 phenyl ring provided a further improvement in agonist activity
(Table 3). The racemic 2-methoxy-6-methyl phenyl analog 29
displayed excellent potency hAPJ/cAMP EC50 = 5 nM, while the
separated atropisomers 30 and 31 were of nearly equal potency of
In conclusion, through an HTS campaign, aryl hydroxy
pyrimidinones were discovered as a new class of small molecules
that provide full agonist activation of the APJ receptor, consistent
with that of the native pep-tide ligand (pyr1)apelin-13. Medicinal

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Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests: