Design and synthesis of boronic acid inhibitors of endothelial lipase

Article abstract of DOI:10.1016/j.bmcl.2011.12.043

Endothelial lipase (EL) and lipoprotein lipase (LPL) are homologous lipases that act on plasma lipoproteins. EL is predominantly a phospholipase and appears to be a key regulator of plasma HDL-C. LPL is mainly a triglyceride lipase regulating (V)LDL levels. The existing biological data indicate that inhibitors selective for EL over LPL should have anti-atherogenic activity, mainly through increasing plasma HDL-C levels. We report here the synthesis of alkyl, aryl, or acyl-substituted phenylboronic acids that inhibit EL. Many of the inhibitors evaluated proved to be nearly equally potent against both EL and LPL, but several exhibited moderate to good selectivity for EL.

Full text of DOI:10.1016/j.bmcl.2011.12.043

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1397–1401
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of boronic acid inhibitors of endothelial lipase
Daniel P. O’Connell a, Daniel F. LeBlanc a, Debra Cromley b, Jeffrey Billheimer b, Daniel J. Rader b,
William W. Bachovchin a,
⇑
a Tufts University School of Medicine, Department of Biochemistry, 136 Harrison Ave., Boston, MA 02111, United States
b Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Endothelial lipase (EL) and lipoprotein lipase (LPL) are homologous lipases that act on plasma lipopro-
teins. EL is predominantly a phospholipase and appears to be a key regulator of plasma HDL-C. LPL is
mainly a triglyceride lipase regulating (V)LDL levels. The existing biological data indicate that inhibitors
selective for EL over LPL should have anti-atherogenic activity, mainly through increasing plasma HDL-C
levels. We report here the synthesis of alkyl, aryl, or acyl-substituted phenylboronic acids that inhibit EL.
Many of the inhibitors evaluated proved to be nearly equally potent against both EL and LPL, but several
exhibited moderate to good selectivity for EL.
Received 25 October 2011
Revised 6 December 2011
Accepted 8 December 2011
Available online 13 December 2011
Keywords:
Endothelial lipase
Boronic acids
Ó 2011 Elsevier Ltd. All rights reserved.
Small molecule inhibitors
HDL-cholesterol
Lipoprotein lipase
Heart disease is the most common cause of death in the United
States.1 High density lipoprotein (HDL) cholesterol represents the
component among the lipid populations that protects against cor-
onary artery disease (CAD) and cardiac events. Whereas serum
concentrations of low density lipoprotein (LDL) cholesterol and tri-
glycerides are positively correlated with risks for developing CAD,
concentrations of HDL-cholesterol are negatively correlated. As
such, it is now estimated that each 1 mg/dL increase in HDL-C lev-
els is accompanied by a corresponding decrease of cardiovascular
risk of 2% in women and 3% in men.2 Studies have also shown
low HDL-C to be an independent risk factor for coronary heart dis-
ease, which includes death by cardiac events, as well as myocardial
infarction and silent infarct.3 Additionally, there is evidence that
HDL-C may play a direct role in protecting from atherosclerosis.
Much of this protection may be the result of HDL-C’s role in the re-
verse cholesterol transport pathway. This generally provides that
cholesterol from peripheral tissues may be loaded onto HDL via
ABCA1 channels to be transported back to the liver either directly
or through CETP-mediated shuttling onto LDL. To this end, factors
that affect the circulating levels of HDL-C are important compo-
nents of the cardiac risk factor mosaic. Included in this list are ther-
apeutic agents such as niacin and torcetrapib, as well as enzymes
of the triglyceride lipase gene family.
identity to human lipoprotein lipase (LPL) and 41% sequence iden-
tity to human hepatic lipase (HL).4,5 The catalytic center, consisting
of a classic serine hydrolase aspartate–histidine–serine motif, is
conserved among these proteins. Additionally, the putative lipid
binding pockets appear conserved as well, indicating that EL likely
interacts with lipid substrate in much the same way that HL and
LPL do. Before interacting with potential substrate, EL remains in
a closed conformation, whereby a 10-amino acid disulfide-linked
lid blocks entrance to the active site. Upon binding lipid, this lid
domain undergoes significant conformational change, to allow
substrate access to the relatively buried catalytic residues.6 While
all three proteins contain a lid, EL appears to have a lid region that
is significantly distinct from the other proteins.7 This suggests that
EL may have a different substrate specificity than either HL or LPL,
and indeed, EL has considerably greater preference for HDL over
other lipoproteins; moreover, HDL is modulated by EL more than
by any other lipase.8 EL preferentially hydrolyses fatty acid esters
from the phospholipid components of HDL. Comparing hydrolysis
of triglyceride substrates to phospholipid substrates, EL demon-
strates a clear preference for phospholipids. In contrast, LPL prefers
hydrolysis of triglyceride substrate to phospholipid substrate over
200-fold more than EL.9
That HDL-C concentration is greatly influenced by EL is clear in
studies that have manipulated its expression levels in vivo. In gene
knock-out studies, mice that have an altered EL genetic profile
have significantly increased levels of HDL-cholesterol: 57% in the
EL ꢀ/ꢀ model, 25% in the EL +/ꢀ model.8 Infusion of wild-type mice
with an anti-EL antibody lead to an increase of HDL-C by 30–50%
over 48 h.10 Perhaps most striking is the effect that EL depletion
The triglyceride lipase gene family is a subset of the a/b hydro-
lase family. Endothelial lipase (EL) is the most recently discovered
member of the triglyceride lipase family, sharing 44% sequence
⇑
Corresponding author. Tel.: +1 617 636 6881; fax: +1 617 636 2409.
E-mail address: william.bachovchin@tufts.edu (W.W. Bachovchin).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.043

1398
D. P. O’Connell et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1397–1401
has on the atherosclerotic ApoE ꢀ/ꢀ mouse model. ApoE ꢀ/ꢀ mice
were bred with EL ꢀ/ꢀ animals to generate a double knockout
strain. In comparison to the ApoE ꢀ/ꢀ model, the double knock-
outs had higher levels of HDL-C and (V)LDL, but nonetheless had
significantly reduced atherosclerotic lesion areas at the aortic
root.11 In this model, then, the abrogation of EL-dependent deple-
tion and modification of HDL effectively rescued the atheroscle-
rotic profile. These last results have been disputed12 to the extent
that the EL ꢀ/ꢀ reversed the atherosclerotic lesion; both studies,
however, are in agreement with respect to the increased HDL-C
effect.
Lipoprotein lipase (LPL) is another member of the lipase gene
family involved in lipoprotein metabolism, particularly of VLDL
and chylomicrons. It is primarily responsible for the liberation of
fatty acids to be utilized as energy by muscle or stored by adipose.
There is a positive correlation between HDL-C levels and LPL activ-
ity.13,14 The hydrolytic action of LPL releases lipids that are trans-
ferred to immature HDL particles. The CETP-mediated exchange
between (V)LDL triglycerides and HDL cholesterol esters is in part
regulated by the relative concentrations of each of these lipid com-
ponents. As such, increased LPL activity extends the half-life of HDL
particles by diminishing the concentration of triglyceride-rich par-
ticles available for a CETP-mediated interaction.15 For these rea-
using O-triflate nitrobenzene (Scheme 1, compounds 2–4) as start-
ing materials. Coupling of the triflate with an alkylboronic acid
using Pd(OAc)2 with the S-PHOS ligand20 produced the
corresponding alkylnitrobenzene (5c–5q) in quantitative yield by
GC–MS. These were reduced with H2 over Pd/C to produce the cor-
responding aniline (6c–6q) in high yield.21 The amino group was
converted to an iodide through diazonium formation with NaNO2
and H2SO4, followed by displacement with KI,22 forming iodoben-
zene compounds 7c–7q.
Synthesis of the pinacol esters was explored to capitalize on
their increased stability relative to free boronic acids. Recent work
has suggested that the pinacol boronate group can be directly in-
serted onto an aryliodide via a transition metal catalyzed reaction.
One reported system (CuI/NaH)23 failed to produce any product in
our hands, but a palladium catalyzed system24 showed much more
potential. Since the S-PHOS ligand proved to be so versatile in ear-
lier synthetic steps, we examined the possibility of using the same
ligand system to couple pinacolborane here. Indeed, Pd(OAc)2/S-
PHOS proved very adept at inserting pinacolborane, often in crude
yields of near 80% (8c–8q). The remaining 20% resulted from addi-
tion of hydride at the aryliodide bond, as determined by GC–MS.
Interestingly, this result was not observed for the synthesis of pina-
col (2-nonylphenyl)boronate. Repeated attempts failed to produce
any boron-containing product. Instead, only unreacted starting
aryliodide 7j was collected. The free boronic acid 9j could only
be synthesized through more traditional lithium-halogen ex-
change, although the yield was very low (10%). For the remaining
alkyl-substituted boronate compounds 8c–8i, removal of the pina-
col protection group was effected by a two step process whereby
the ester was first converted to the potassium trifluoroborate
salt.25 This salt was recrystallized from warm acetone and then
converted to the free boronic acid by use of a fluorophile, chlorotri-
methylsilane. Generally, a 40% overall recovery of free boronic acid
from the pinacol ester was obtained via this unoptimized method-
ology. This was not the case for biarylboronate esters, 8k–8q, as
these compounds showed very low solubility in methanol during
the conversion to the trifluoroborate salt. As such, these com-
pounds were not converted to free acids, but rather examined in
assays as the pinacol esters.
sons, LPL is viewed as
a powerful protector against both
development of atherosclerosis and decreasing levels of HDL-C.
LPL shares considerable sequence, and presumably structural,
homology with other members of this family, such as EL and
HL.16 Therefore, cross-inhibition of LPL would be detrimental to
the goals of increasing levels of HDL-C or decreasing risks of CAD.
Two assay systems were used to explore the inhibition of EL and
LPL. A vesicle-based system9 allowed for the exploration of the
inhibition of these enzymes as they would undergo interfacial
catalysis, as would be expected under physiological conditions.
The micelle assay,17 on the other hand, permitted the exploration
of effects of inhibition directly at the active sites, as the mechanism
of interfacial catalysis is effectively removed under such condi-
tions.18 Derivatives of palmitic acid containing various electro-
philic traps known to inhibit hydrolases that utilize Asp-His-Ser
triads in their active sites were synthesized according to literature
precedents. Table 1 illustrates that among these compounds, the
boronic acid 1f demonstrated the greatest potency at our screening
A carboxylate-containing boronate compound was synthesized
in the hopes of capitalizing on the different substrate preferences
between phospholipid-hydrolyzing EL and triglyceride-hydrolyz-
ing LPL. For this compound, the order of synthetic manipulation
was changed to insert the aryliodide before benzylic bromination
as illustrated in Scheme 2. Once the enolate condensation reaction
had been accomplished, insertion of the pinacol boronate pro-
ceeded without loss of the tert-butyl ester protection group, effect-
ing compound 15. This proved a highly fruitful strategy as the last
several steps of this synthetic scheme occurred in very satisfactory
yields (60% for pinacolboronate insertion, compound 15, and 70%
concentration of 50 lM, inhibiting 90% of EL activity. The trifluoro-
methyl ketone 1e was the second most potent, at 56% EL inhibition.
No other electrophile demonstrated significant inhibition. While
not selective, these data substantiated an exploration of boronic
acids as a class of inhibitory molecules. Indeed, boronic acids have
been shown to be reversible active site inhibitors of many serine
hydrolases.19
Phenylboronic acid derivatives were then tested as inhibitors.
Derivatization was accomplished with Suzuki coupling reactions
NO2
NO2
NH2
c
Table 1
a
b
Inhibition of EL and LPL by electrophilic derivatives of palmitic acid
TfO
R
R
CH3 ꢀ ðCH2Þ14 ꢀ X
2-4
5c-5p
6c-6p
Compound
X
% EL inhibitiona
%LPL inhibition
O
B
OH
B
1a
1b
1c
1d
1e
1f
C(O)CH2Cl
CN
CHO
C(O)CHN2
C(O)CF3
B(OH)2
10
4
7
ꢀ22
56
90
ꢀ10
14
I
d
O
e
OH
ꢀ1
R
R
R
20
14
63
7c-7p
8c-8p
9c-9k
a
Percent inhibition of EL or LPL at 50 lM concentration in the vesicle assay.
Scheme 1. Reagents: (a) R-B(OH)2, Pd(OAc)2, S-PHOS, K3PO4–H2O, PhCH3. (b) H2,
Pd/C, EtOH. (c) (1) NaNO2, HCl, ice, H2O. (2) KI, H2O. (d) Pinacolborane, Pd(OAc)2, S-
PHOS, NEt3, Dioxane. (e) (1) KHF2, MeOH. (2) TMSCl, H2O, CH3CN.
Values are expressed as a percent of activity of each enzyme incubated with DMSO
control.

D. P. O’Connell et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1397–1401
NO2
1399
I
I
a,b,c
d
Br
Br
12
13
e
O
B
O
B
I
O
O
g
f
O
O
O
O
O
OH
16
15
14
Scheme 2. Reagents: (a) Ph-B(OH)2, Pd(OAc)2, S-PHOS, K3PO4, nBuOH, 100 °C. (b) Pd(C), H2 5 bars, EtOH. (c) NaNO2, HCl, KI. (d) NBS, AIBN, CCl4. (e) tert-butyl acetate, LDA,
THF, ꢀ78 °C. (f) Pinacolborane, Pd(OAc)2, S-PHOS, triethylamine, dioxane, 80 °C. (g) TFA, CH2Cl2.
for tert-butyl ester deprotection, compound 16). This reflects the
stability of the pinacol ester to anhydrous acidic conditions. This
speaks very promisingly for future use of this synthetic route with
other functional group moieties.
Unlike in the vesicle assay, these same compounds showed
increasing inhibition against LPL as a function of chain length.
Longer chain lengths were still associated with increased EL selec-
tivity in the micelle assay, but the magnitude of the effect was mu-
ted, as shown by 9f, being 14-fold selective and thus, three-fold
less discriminating than in the vesicle assay.
Phenylboronic acid derivatives substituted at the 2- and 3-posi-
tion showed considerably less potency against both EL and LPL
than similar compounds substituted at the 4-position. Specifically,
3-pentylphenylboronic acid (9h) was 13-fold less potent against EL
than 4-pentylphenylboronic acid (9d) in the vesicle assay and 47-
fold less potent against EL in the micelle assay. Substitution at the
2-position, as in 2-nonylphenylboronic acid (9j) effected an espe-
cially poor inhibitor of both enzymes in both assay systems. This
is in direct contract to the moderate inhibitor, 3-nonylphenylbo-
ronic acid (9i), and the more potent 4-nonylphenylboronic acid
(9f). These results imply specific patterns for substituents on the
ring relative to the boronic acid, in decreasing order of potency:
1,4 > 1,3 > 1,2.
As shown in Table 2 and 4-substituted phenylboronic acids 9a–
9g were potent inhibitors of both EL and LPL. In the vesicle assay,
inhibition of EL increased with increasing chain length, reaching
a plateau near a tail of length 7 carbons. Alkyl chains of 7-, 9-,
and 11-carbons (9e–9g) were comparable in their potency of EL
inhibition. In contrast, an inverse relationship between inhibitory
prowess and carbon chain length was demonstrated for LPL. From
propyl to undecyl (9c–9g), the increase in alkyl chain length corre-
sponded with an increase in IC50 value against LPL. This lead to an
increase in the EL selectivity measure, defined as a ratio of the IC50
against LPL to the IC50 against EL for a given compound, reaching a
maximum of 42-fold with compound 9f. Because the EL IC50
plateaued starting at the 7-carbon chain (9e), this increase in EL
selectivity was due entirely to the increase in IC50 against LPL for
compounds of longer chain length. In the micelle assay, these com-
pounds showed increasing potency against EL with increasing
chain length, in agreement with the data from the vesicle assay.
The pinacol boronate esters showed effective potency against
both enzymes, as shown in Table 3, and were well correlated with
Table 2
Inhibition of endothelial lipase and lipoprotein lipase by phenylboronic acids
OH
B
OH
R
EL,vesicle
LPL,vesicle
EL,micelle
LPL,micelle
Compound
R
IC50
(l
M)a
IC50
(l
M)
EL Selectivity, vesicleb
IC50
(l
M)c
IC50
(l
M)
EL Selectivity, micelled
9a
9b
9c
9d
9e
9f
9g
9h
9i
4-Methyl
4-Ethyl
17
11
9
9
8.0
15.0
30.0
42.0
50
50
>50
ꢁ50
0.5
0.3
4
15
18
42
25
4
22
19
4.0
0.47
0.32
0.1
0.2
22
25
20
1.1
1.0
3.1
8.0
28
4-Propyl
4-Pentyl
4-Heptyl
4-Nonyl
4-Undecyl
3-Pentyl
3-Nonyl
2-Nonyl
2.0
1.0
1.7
1.0
2.0
12.8
2.8
50
12.5
3.8
9.0
1.4
1.5
85
14
7.5
3.8
19
>20
5.0
11
95
>500
e
9j
—
>50
a
b
c
IC50 values reported as the average of two independent vesicle based experiments, each performed in duplicate.
EL selectivity, vesicle is defined as the ratio of LPL to EL IC50 values as measured in the vesicle assays and is unitless.
IC50 values reported as the average of two independent micelle based experiments, each performed in duplicate.
EL Selectivity, micelle is defined as the ratio of LPL to EL IC50 values as measured in the micelle assays and is unitless.
Indeterminate.
d
e

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D. P. O’Connell et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1397–1401
the free boronic acid. These compounds generally showed excel-
lent inhibition of EL, with IC50 values in the low micromolar range.
Conversely, their inhibition of LPL varied from the low to mid
micromolar range. The most striking difference was between pina-
col (4-phenylphenyl)boronate (8k) and pinacol (4-(4-fluoro-
phenyl)phenyl)boronate (8l), where a 12.5-fold difference in LPL
inhibition was seen in IC50 values between the fluorinated and
non-fluorinated species, leading directly to a 7.7-fold enhancement
in selectivity for EL. While the magnitude of the effect was abro-
gated somewhat in the micelle assay, the difference, 2.5-fold more
EL selective with the fluorinated species, was still noted. Interest-
ingly, the heterocyclic boronate esters were also inhibitory against
EL and LPL. Compounds 8m–8p were all modest inhibitors with
varying selectivity between the two enzymes, but no one in partic-
ular was a specifically outstanding compound. Finally, the car-
boxyl-containing compound 16 showed little inhibition against
either protein, despite the 4-phenyl substituent seen in the compa-
rably much more potent compounds (8k) and (8l). This result was
seen with both assay systems, implying that the result comes from
a specific detrimental enzyme–inhibitor interaction, rather than an
incompatible inhibitor–assay system interaction. The most likely
candidate for this unfavorable interaction is the carboxylate; it re-
mains unknown, however, whether the regiochemistry on the ring,
or the charge itself, was the responsible component.
In this study, we attempted to design potent, selective inhibi-
tors of EL. Our vesicle-based assay system indicated that such
selectivity is possible, as increases in the chain length of alkyl-
substituted phenylboronic acids, particularly at the 4-position,
conferred increased EL selectivity. The nature of this trend was
not due solely to increasing potency against EL, however. Instead,
this selectivity was primarily obtained through the diminishing
potency of these inhibitors against LPL with increasing chain
length in the 4-position. This clear inverse relationship between
inhibitor potency against LPL and alkyl chain length was not ob-
served for the micelle assay. Rather, in the micelle assay, increas-
ing chain length conferred increased potency of inhibitors 9a–9g
against both EL and LPL. Selectivity for EL was still observed,
but in the case of 9f, selectivity was three-fold lower in the mi-
celle assay than in the vesicle assay (14- vs 42-fold, respectively).
The additional selectivity in the vesicle assay can be explained in
part by the nature of the lipase-substrate interaction. The lid re-
gion is made effectively irrelevant by the detergent assay, allow-
ing a compound free access to the active site.18 With the active
site freely accessible, an inhibitor may appear to be potent, but re-
plies upon intrinsic binding differences between the two proteins
for selectivity. Thus, compound 9f is potent against both enzymes’
active sites with 14-fold selectivity, as shown by the IC50 values in
the micelle assay (0.1 and 1.4 lM, respectively). By contrast, in
the vesicle system, LPL may fail to undergo proper conformational
changes at its lid to allow 9f access to the LPL active site to the
degree seen in the micelle assay,13 contributing to the increased
selectivity for EL in the vesicle assay. Exploiting selective access
to the enzyme active site as a means of effecting discriminatory
inhibition may prove to be a fruitful strategy for inhibiting such
closely related enzymes. When proteins of the same family such
as EL and LPL have such homologous active sites, it is essential
to move beyond those regions to exploit any possible differences.
This lid-based discrimination of the active site may prove to be
the most expedient path toward development of potent, selective
inhibitors of EL.
Goodman et al. have reported the synthesis of a library of EL and
LPL inhibitors based on a sulfonylurea backbone.26 Therein, com-
pounds were described with variable potency against either en-
zyme, ranging from 0.04 lM to the assay maximum of 50 lM.
However, while not extensively discussed, it is clear that obtaining
selectivity was also a challenge with this sulfonylurea series, as the
most selective compound reported was only 15-fold selective for
EL. Clearly, the challenge of EL selective inhibition must be over-
come regardless of potency before any molecule would be consid-
ered
a success. Indeed, both Goodman’s 15-fold selective
sulfonylurea and our own 42-fold selective boronic acid set the
stage for the discovery of increasingly selective inhibitors. The dis-
covery of such a molecule would provide a novel means by which
to specifically raise HDL-C. In light of the failure of torcetrapib to be
Table 3
Inhibition of endothelial lipase and lipoprotein lipase by pinacol(phenylboronate) esters
O
B
O
R
EL,vesiclea
LPL,vesicle
EL,micellec
LPL,micelle
Compound
R
IC50
(l
M) IC50
(l
M) EL Selectivity, vesicleb IC50
(l
M) IC50
25
(l
M) EL Selectivity, micelled
8c
8d
8e
8f
8g
8h
8k
8l
8m
8n
8o
8p
8q
16
4-Propyl
4-Pentyl
4-Heptyl
4-Nonyl
4-Undecyl
3-Pentyl
4-Phenyl
4-(4-Fluorophenyl)
4-Furan-2-yl
4-Thiophen-2-yl
4-Furan-3-yl
4-Thiophen-3-yl
4-Naphth-2-yl
4-Ph-3-
5.0
2.6
3.5
2.5
4.5
4.2
1.0
1.6
1.9
1.9
2.8
1.3
2.0
95
25
50
55
50
>50
45
4.4
55
9.6
7
5
6.0
1.1
1.1
1.0
1.4
35
1.0
1.1
1.3
1.6
2.9
3.1
1.7
300
4.1
19
17
15
11
2.8
12
30
27
25
11
12
8.8
1.7
19
16
20
21
19
15
15
100
12
33
35
40
33
e
—
11
4.4
34
5
3.7
5.4
10
11
1.2
15
13
22
120
36
15
ꢂ500
((CH2)2CO2H)
a
b
c
IC50 values reported as the average of two independent vesicle based experiments, each performed in duplicate.
EL selectivity, vesicle is defined as the ratio of LPL to EL IC50 values as measured in the vesicle assays and is unitless.
IC50 values reported as the average of two independent micelle based experiments, each performed in duplicate.
EL Selectivity, micelle is defined as the ratio of LPL to EL IC50 values as measured in the micelle assays and is unitless.
Indeterminate
d
e

D. P. O’Connell et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1397–1401
1401
9. McCoy, M. G.; Sun, G. S.; Marchadier, D.; Maugeais, C.; Glick, J. M.; Rader, D. J. J.
Lipid Res. 2002, 43, 921.
10. Jin, W.; Millar, J. S.; Broedl, U.; Glick, J. M.; Rader, D. J. J. Clin. Invest. 2003, 111,
357.
approved as an HDL-C raising therapeutic, new mechanisms such
as EL inhibition have become increasingly attractive.
11. Ishida, T.; Choi, S. Y.; Kundu, R. K.; Spin, J.; Yamashita, T.; Hirata, K.; Kojima, Y.;
Yokoyama, M.; Cooper, A. D.; Quertermous, T. J. Biol. Chem. 2004, 279, 45085.
12. Ko, K. W.; Paul, A.; Ma, K.; Li, L.; Chan, L. J. Lipid Res. 2005, 46, 2586.
13. Merkel, M.; Eckel, R. H.; Goldberg, I. J. J. Lipid Res. 2002, 43, 1997.
14. Wittrup, H. H.; Tybjaerg-Hansen, A.; Nordestgaard, B. G. Circulation 1999, 99,
2901.
Acknowledgments
The authors thank Jack Lai and Wen Gen Wu for thoughtful dis-
cussions on synthesis and preparation of compounds. We thank
Arisaph Pharmaceuticals (Boston, MA) for financial support.
15. Goldberg, I. J. J. Lipid Res. 1996, 37, 693.
16. (a) Kobayashi, Y.; Nakajima, T.; Inoue, I. Eur. J. Biochem. 2002, 269, 4701; (b) van
Tilbeurgh, H.; Roussel, A.; Lalouel, J. M.; Cambillau, C. J. Biol Chem 1994, 269,
4626.
Supplementary data
17. Mitnaul, L. J.; Tian, J.; Burton, C.; Lam, M. H.; Zhu, Y.; Olson, S. H.; Schneeweis, J.
E.; Zuck, P.; Pandit, S.; Anderson, M.; Maletic, M. M.; Waddell, S. T.; Wright, S.
D.; Sparrow, C. P.; Lund, E. G. J. Lipid Res. 2007, 48, 472.
Supplementary data (Reference data for known compounds,
NMR and MS data for new compounds, and EL and LPL assay.) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2011.12.043.
18. González-Navarro, H.; Bañó, M. C.; Abad, C. Biochemistry 2001, 40, 3174.
19. For examples of boronic acid inhibitors, see: (a) Connolly, B. A.; Sanford, D. G.;
Chiluwal, A. K.; Healey, S. E.; Peters, D. E.; Dimare, M. T.; Wu, W.; Liu, Y.; Maw,
H.; Zhou, Y.; Li, Y.; Jin, Z.; Sudmeier, J. L.; Lai, J. H.; Bachovchin, W. W. J. Med.
Chem. 2008, 51, 6005; (b) Flentke, G. R.; Munoz, E.; Huber, B. T.; Plaut, A. G.;
Kettner, C. A.; Bachovchin, W. W. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 1556; (c)
Kettner, C. A.; Shenvi, A. B. J. Biol Chem. 1984, 259, 15106; (d) Adams, J.; Behnke,
M.; Chen, S.; Cruickshank, A. A.; Dick, L. R.; Grenier, L.; Klunder, J. M.; Ma, Y. T.;
Plamondon, L.; Stein, R. L. Bioorg. Med. Chem. Lett. 1998, 8, 333.
20. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 4685.
21. Wehner, V.; Jager, V. Angew. Chem. Int. Ed. Engl. 1990, 29, 1169.
22. Sienkowska, M.; Benin, V.; Kaszynski, P. Tetrahedron 2000, 56, 165.
23. Zhu, W.; Ma, D. Org. Lett. 2006, 8, 261.
24. Baudoin, O.; Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67, 1199.
25. Yuen, A. K. L.; Hutton, C. A. Tetrahedron Lett. 2005, 46, 7899.
26. Goodman, K. B.; Bury, M. J.; Cheung, M.; Cichy-Knight, M. A.; Dowdell, S. E.;
Dunn, A. K.; Lee, D.; Lieby, J. A.; Moore, M. L.; Scherzer, D. A.; Sha, D.; Suarez, D.
P.; Murphy, D. J.; Harpel, M. R.; Manas, E. S.; McNulty, D. E.; Annan, R. S.;
Matico, R. E.; Schwartz, B. K.; Trill, J. J.; Sweitzer, T. D.; Wang, D. Y.; Keller, P. M.;
Krawiec, J. A.; Jaye, M. C. Bioorg. Med. Chem. Lett. 2009, 19, 27.
References and notes
1. Kochanek, K. D.; Murphy, S. L.; Anderson, R. N.; Scott, C. Natl. Vital Stat. Rep.
2004, 53, 1.
2. Martinez, L. O.; Jacquet, S.; Tercé, F.; Collet, X.; Perret, B.; Barbaras, R. Cell. Mol.
Life Sci. 2004, 61, 2343.
3. Sharrett, A. R.; Bllantyne, C. M.; Coagy, S. A.; HHeiss, G.; Sorlie, P. D.; Catellier,
D.; Patsch, W. Circulation 2001, 104, 1108.
4. Hirata, K.; Dichek, H. L.; Cioffi, J. A.; Choi, S. Y.; Leeper, N. J.; Quintana, L.;
Kronmal, G. S.; Cooper, A. D.; Quertermous, T. J. Biol. Chem. 1999, 274, 14170.
5. Jaye, M.; Lynch, K. J.; Krawiec, J.; Marchadier, D.; Maugeais, C.; Doan, K.; South,
V.; Amin, D.; Perrone, M.; Rader, D. J. Nat. Genet. 1999, 21, 424.
6. Wong, H.; Schotz, M. C. J. Lipid Res 2002, 43, 993.
7. Choi, S. Y.; Hirata, K.; Ishida, T.; Quertermous, T.; Cooper, A. D. J. Lipid Res 2002,
43, 1763.
8. Ishida, T.; Choi, S.; Kundu, R. K.; Hirata, K.; Rubin, E. M.; Cooper, A. D.;
Quertermous, T. Clin. Invest. 2003, 111, 347.