Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase

Article abstract of DOI:10.1021/acsmedchemlett.8b00424

Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe

Full text of DOI:10.1021/acsmedchemlett.8b00424

Letter
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Sulfonylated Benzothiazoles as Inhibitors of Endothelial Lipase
James A. Johnson,*,† George Tora,† Zulan Pi,† Monique Phillips,† Xiaohong Yin,‡ Richard Yang,‡,¶
Lei Zhao,‡ Alice Y. Chen,‡ David S. Taylor,‡ Michael Basso,‡ Anne Rose,⊥ Kamelia Behnia,⊥,○
Joelle Onorato,⊥ Xue-Qing Chen,§ Lynn M. Abell,∥,◆ Hao Lu,∥,□ Gregory Locke,∥
Christian Caporuscio,# Michael Galella,∇ Leonard P. Adam,‡ David Gordon,‡ Ruth R. Wexler,†
and Heather J. Finlay†
Departments of †Discovery Chemistry, ‡Biology, §Pharmaceutics, ∥Mechanistic Biochemistry, ⊥Preclinical Candidate Optimization,
∇
#Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New
Jersey 08543-5400, United States
S
* Supporting Information
ABSTRACT: Endothelial lipase (EL) selectively metabolizes high density
lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL
concentration in preclinical animal models and was targeted as a potential
treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety
to a benzothiazole series of EL inhibitors resulting in increased potency versus EL.
Optimization for selectivity versus hepatic lipase and pharmacokinetic properties
resulted in the discovery of 24, which showed good in vitro potency and
bioavailability but, unexpectedly, did not increase HDL in the mouse
pharmacodynamic model at the target plasma exposure.
KEYWORDS: Endothelial lipase, HDL, atherosclerosis
ndothelial lipase (EL) is a member of the lipase gene
family, which includes hepatic lipase (HL), lipoprotein
EL selective inhibitors represented by 1 (reported EL IC50
=
E
0.24 μM) was described (Figure 1).26 Compound 1, referred
lipase (LPL), and pancreatic lipase (PL).1 These lipases
modulate lipid levels in circulating plasma by metabolism of
phospholipids and triglycerides. EL selectively hydrolyzes
phospholipids on the surface of high density lipoprotein
(HDL) leading to particle degradation, whereas other lipases
in the family are selective for triglycerides.2 Epidemiology
studies have shown that HDL concentration is inversely
correlated with coronary heart disease.3,4 This may be due to
the ability of HDL to promote cholesterol efflux from
atherosclerotic plaque as part of reverse cholesterol transport
(RCT).5 In addition, HDL has antioxidant and anti-
inflammatory effects that are atheroprotective.6,7 Although
clinical outcomes of increasing HDL by inhibition of
cholesterol ester transfer protein (CETP) have shown marginal
benefit in the best case,8,9 evaluation of alternative biological
targets, which raise HDL levels, are an area of ongoing
research.10,11
Figure 1. Recently disclosed EL inhibitors.
EL knockout studies12−14 and anti-EL antibodies15 in mice
demonstrated that inhibiting EL function resulted in increased
plasma HDL levels. These studies, together with the
epidemiological data, led to targeting small molecule inhibitors
of EL for the potential treatment of atherosclerosis.16−19 Due
to the high sequence homology of the catalytic center for
members of this family, selective inhibition of EL has been a
historical challenge for small molecules.20,21 Inhibition of LPL
leads to decreased levels of HDL, and inhibition of HL may
lead to increased levels of cholesterol depositing low density
lipoprotein (LDL).22−25 Recently, a series of anthranilic acid
to as XEN445, was found to raise HDLc concentrations by
16% (p < 0.05) when dosed for 3 days at 30 mpk b.i.d. in wild-
type mice (the plasma concentration at 16 h post the last dose
was 9.9 μM with a free fraction corrected exposure of 1.1
μM).26 We have recently disclosed a series of EL selective
inhibitors represented by 2 and found no effect on HDLc
concentrations in a mouse model when dosed at 50 mpk for 5
Received: September 14, 2018
Accepted: November 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00424
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ACS Medicinal Chemistry Letters
Letter
days q.d.27 Subsequently, we developed assays for EL
inhibition in the presence of mouse plasma and human
serum. Compound 2 did not demonstrate measurable
inhibition of EL in these assays at the highest concentration
tested of 952 μM providing a possible explanation for the lack
of pharmacodynamic effect. Concurrently, a series of
benzothiazole EL inhibitors were reported, which have a
methylene bridge to a 1,3,4-oxadiazole represented by 3
(reported EL IC50 = 6 nM).28 We found compound 3 had
encouraging levels of activity in the mouse plasma and human
serum assays (IC50 = 0.40−0.42 μM), which led to our interest
in further exploring the series by substitution at the methylene
bridge position.
12 μM) and PL (IC50 > 37 μM) albeit relatively poor
selectivity versus HL (IC50 = 53 nM). High selectivity versus
LPL and PL were observed for other compounds tested in this
series. In comparison, we found the weight loss drug Orlistat
was a potent inhibitor of EL (IC50 = 6 nM) as well as HL, LPL,
and PL (IC50 = 3, 66, and 6 nM, respectively). Compound 7
also demonstrated inhibition of EL in the presence of human
serum (IC50 = 47 nM) and mouse plasma (IC50 = 170 nM).
Minimal effect on potency or selectivity was achieved by
modifications to the sulfone substituent such as increasing the
size (isopropyl 8), lipophilicity (trifluoropropyl 9), polarity
(methoxyethyl 10), or by introduction of aromatic groups
(benzyl 11).
The benzyl sulfone 11 was chosen for further SAR
development on the C6 phenyl ring based on its improved
potency in mouse plasma (IC50 = 77 nM) while maintaining
similar potency in human serum (IC50 = 76 nM). To efficiently
explore SAR at the C6 position of the benzothiazole, the
sequence of steps was altered to enable Suzuki cross coupling
as the final step to generate compounds 15−19 (Scheme 2).
Substitution of chlorine at the meta or meta and para
positions (15, 16) maintained potency but did not improve
selectivity versus HL (Table 1). The methyl carbamate in the
para position (17) had modest selectivity. The most selective
compound versus HL was dimethyl amide 18, but a significant
amount of EL potency was lost in the presence of human
serum and mouse plasma. Morpholine amide 19 had the best
balance of selectivity and activity while maintaining potency in
the presence of human serum but showing reduced potency in
the mouse plasma assay.
Compound 3 was prepared by the general method described
(Scheme 1).29 Regioselective sulfonylation gave compounds
a
Scheme 1. Synthesis of Sulfonyl Compounds
With encouraging activity and selectivity for the series, we
next determined if the mechanism of EL inhibition was
reversible. Compound 11 and EL were preincubated to form
an enzyme−inhibitor complex at serial concentrations.
Subsequent dialysis and activity determination of the free
enzyme was measured at 24 and 48 h time points (Figure 3). It
was found that the activity increased with time and dilution of
11 (52% recovered enzyme activity at 48 h with 3 μM
concentration of 11), indicating the inhibition of EL to be
reversible.
Having established potency, selectivity, and reversibility, the
series was advanced to mouse pharmacokinetic studies to
determine exposures (Table 2). To target IC90 coverage, we
projected a target plasma through concentration of five times
the mouse plasma IC50 to maintain EL inhibition. Oral dosing
of the sulfamides 7 and 11 (mouse plasma EL IC50 = 0.17 and
0.077 μM, respectively) at a 10 mpk dose gave exposures
between 0.01 and 0.02 μM at the 7 h time point. These
exposure levels did not meet target concentrations for 7 and 11
(>0.8 and >0.4 μM, respectively). The dose of 10 mpk was at
the limit of solubility in the vehicle, and b.i.d. dosing was not
expected to provide target plasma concentrations. Further
modifications to the series were therefore required to attain
target exposure.
a
Reagents and conditions: (a) NH2NH2, MeOH (94%); (b) N-
BocGly, T3P, DIEA, dioxane, EtOAc, reflux (65%); (c) (1) TFA,
DCM (94%); (2) N-TDDSA, DCM (95%); (3) TFA, DCM (74%);
(d) (1) NaH or NaHMDS, DMF, 0 °C; (2) RSO2Cl (yields in
parentheses).
7−11, the site of substitution was confirmed by X-ray
crystallography. Compound 7 crystallized in the tautomeric
form with the double bond in conjugation with the sulfone,
imparting a hydrogen bond (pKa = 7.4) between the
benzothiazole and the oxadiazole (Figure 2).
Figure 2. Crystal structure of 7.
To increase oral exposure by reducing the number of
rotatable bonds, cyclic isosteres of the sulfamide group were
prepared in the form of hydantoins and thiazolidinediones by
utilizing the requisite acids in the oxadiazole cyclization step
(Scheme 3).30,31 Single isomers of hydantoins 22 and 23 could
be obtained by separation of the corresponding enantiomers
after oxadiazole formation. The chiral center of the
thiazolidinedione epimerized readily at room temperature.
Therefore, 21 and 24 were tested as mixtures of isomers.
Inhibition of EL and other members of the triglyceride lipase
family was evaluated using a fluorogenic substrate assay (Table
1).27 EL activity was also measured in the presence of human
serum to account for protein binding and other serum effects,
as well as in plasma of the mouse pharmacodynamic model.
Methyl sulfone 7 showed very good in vitro potency versus EL
(IC50 < 10 nM) with excellent selectivity versus LPL (IC50
=
B
DOI: 10.1021/acsmedchemlett.8b00424
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ACS Medicinal Chemistry Letters
Letter
a
Table 1. Sulfone and C6 Phenyl SAR
a
Inhibition is measured in duplicate at three concentrations, and the mean values are used to calculate the IC50 values.
a
Scheme 2. Substitution of C6 Phenyl
Figure 3. Reversibility experiments with compound 11.
a
Table 2. Mouse Oral PK Properties
compd
dose (mpk)
Cmax (μM)
C7h (μM)
C24h (μM)
b
7
10
10
0.30
2.3
0.01
0.02
<LLQ
0.01
a
Reagents and conditions: (a) N-BocGly, T3P, DIEA, dioxane,
b
11
EtOAc, reflux (73%); (b) TFA, DCM (96%); (c) N-TDDSA,
pyridine, DCM (79%); (d) (1) NaHMDS, THF, −78 °C; (2)
BnSO2Cl (45%); (e) (1) boronic acid, Pd(PPh3)4, 2N Na2CO3,
dioxane, 90 °C; (2) TFA, DCM (yield over two steps in parentheses)
a
b
Data from fasted, male, C57BL/6 mice (n = 3). Vehicle: EtOH/
PEG400/Cremophor EL (10/60/30).
combined with the C6 phenyl morpholine amide (22 and 23),
100-fold selectivity versus HL was obtained. However, both
isomers lost significant potency versus EL in the presence of
human serum and mouse plasma. Thiazolidinedione 24 had
Hydantoin 20 and thiazolidinedione 21 were found to have
good potency for EL but offered no improvement in selectivity
for EL versus HL (Table 3). When the hydantoin was
C
DOI: 10.1021/acsmedchemlett.8b00424
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ACS Medicinal Chemistry Letters
Letter
a
a
Scheme 3. Sulfamide Replacements
Table 4. Mouse Oral PK Properties
compd
dose (mpk)
10
Cmax (μM)
C7h (μM)
C24h (μM)
b
24
2.0
ND
0.90
0.41 @ 8 h
0.17
0.17
b
c
24
50
a
b
Data from fasted, male, C57BL/6 mice (n = 3). Vehicle: EtOH/
c
PEG400/Water (10/60/30). Dosed as homogeneous suspension.
exposures to the 10 mpk dose at the 24 h time point, a
consequence of the limited solubility.
Attempts to further increase the exposure of 24 using spray
dried dispersion techniques were unsuccessful. Nevertheless,
sufficient EL inhibition was expected upon administration of
thiazolidinedione 24 at a 50 mpk dose over a 24 h time course,
and the compound was advanced to the mouse PD model.
Wild-type mice were orally dosed with 24 at 50 mpk q.d. for 2
days. Blood samples were taken at 6 h post final dose and
subjected to FPLC analysis. Compound 24 did not
demonstrate any increase in total plasma cholesterol or
phospholipids with plasma concentrations of 0.54 μM at 30
h. The lack of pharmacodynamic response was unexpected and
may indicate a requirement for higher levels of coverage over
the IC50 than was achieved with compound 24.
In summary, a series of potent, selective, and reversible EL
inhibitors was identified with oral bioavailability in mouse.
Despite achieving exposure multiples above the IC50, no
increase in HDL was observed for compound 24 in the mouse
model. Further optimization of physicochemical and pharma-
cokinetic properties will be the topic of future disclosures.
a
Reagents and conditions: (a) RCO2H, T3P, DIEA, dioxane, EtOAc,
reflux (26% for 20, 70% for 21); (b) (1) NaHMDS, THF, −78 °C;
(2) CH3SO2Cl (39% for 20, 26% for 21); (c) RCO2H, T3P, DIEA,
dioxane, EtOAc, reflux (26% for 22 and 24% for 23 after chiral HPLC
separation, 72% for 23); (d) (4-(morpholine-4-carbonyl)phenyl)-
boronic acid, SiliaCat DPP-Pd or Pd(PPh3)4, K3PO4, dioxane, water,
120 °C (64% for 22, 71% for 23, 25% for 24); (e) (1) NaHMDS,
THF, −78 °C; (2) CH3SO2Cl (41% for 22, 49% for 23, 37% for 24).
a
Table 3. Hydantoin and Thiazolidinedione Series SAR
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00424.
■
S
Synthetic procedures, analytical data, biological and
reversibility assay details, pharmacokinetic procedures,
and graphical representation of PD results (PDF)
Accession Codes
Cambridge Crystallographic Data Centre (CCDC) number for
Compound 7: 1866355.
EL IC50
HL IC50
hSerum EL IC50
mPlasma EL IC50
AUTHOR INFORMATION
Corresponding Author
*E-mail: james.a.johnson@bms.com.
ORCID
James A. Johnson: 0000-0003-4969-5280
Heather J. Finlay: 0000-0003-2309-0136
compd
(μM)
(μM)
(μM)
(μM)
■
20
21
22
23
24
<0.010
<0.010
0.012
0.065
<0.010
0.053
<0.010
1.9
1.4
0.45
0.16
0.91
1.5
6.0
<0.022
0.38
0.053
2.7
3.1
0.094
a
Inhibition is measured in duplicate at three concentrations, and the
mean values are used to calculate the IC50 values.
Present Addresses
○(K.B) Glaxosmithkline PRR DPU, 1250 S Collegeville Rd,
Collegeville, PA 19426, United States.
◆(L.A.) Agios Pharmaceuticals, 88 Sidney Street, Cambridge
MA 02139, United States.
acceptable selectivity for EL versus HL and maintained
potency in human serum and mouse plasma, and was advanced
to pharmacokinetic studies.
Oral dosing of thiazolidinedione 24 in mouse at 10 mpk
gave exposures of 0.90 μM at 7 h and 0.17 μM at 24 h
corresponding to 40-fold and 7-fold over the mouse plasma
IC50, respectively (Table 4). Increasing the dose of 24 to 50
mpk required administration as a suspension and gave similar
¶(R.Y.) Sollers Institute, 55 Parsonage Road, Edison NJ 08837,
United States.
□(H.L.) EMD Serono Research and Development, 45
Middlesex Turnpike, Billerica, MS 01821, United States.
Author Contributions
All authors have given approval to the final version of the
manuscript.
D
DOI: 10.1021/acsmedchemlett.8b00424
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ACS Medicinal Chemistry Letters
Letter
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Notes
The authors declare no competing financial interest.
̈
Doring, A.; Thorand, B.; Li, M.; Reilly, M. P.; Koenig, W.; Samani, N.
ACKNOWLEDGMENTS
■
J.; Rader, D. J. Dense genotyping of candidate gene loci identifies
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The authors would like to thank Dr. Arvind Mathur, Rick
Rampulla, and colleagues at Department of Discovery
Synthesis at Biocon Bristol-Myers Squibb RD Center for the
preparation of intermediates. We thank Robert Langish and
Linping Wang for analytical support and Chris Freeden for
preclinical development support.
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ABBREVIATIONS
■
N-BocGlym, N-(tert-butoxycarbonyl)glycine; T3P, 1-propane-
phosphonic acid cyclic anhydride; DIEA, diisopropylethyl-
amine; EtOAc, ethyl acetate; N-TDDSA, N-(tert-butoxycar-
bonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-
ylsulfonyl]azanide; NaHMDS, sodium hexamethyldisilazane;
TFA, trifluoroacetic acid; DCM, dichloromethane; NaH,
sodium hydride; THF, tetrahydrofuran; DPP-Pd, diphenyl-
phosphine palladium(II);; DMF, dimethylformamide; HPLC,
high-performance liquid chromatography; b.i.d., twice a day;
q.d., once a day; mpk, milligram of compound per kilogram of
body weight; p.o., by mouth; PD, pharmacological dynamics;
FPLC, fast protein liquid chromatography
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