Discovery of potent and orally available malonyl-CoA decarboxylase inhibitors as cardioprotective agents

Article abstract of DOI:10.1021/jm0605029

Discovery of 5-(1.1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5- dihydroisoxazole-3-carboxamides as a new class of malonyl-coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl 3-(5-(1,1,1.3,3,3- hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroi

Full text of DOI:10.1021/jm0605029

J. Med. Chem. 2006, 49, 4055-4058
4055
a
8
Discovery of Potent and Orally Available
Malonyl-CoA Decarboxylase Inhibitors as
Cardioprotective Agents
MCA is a potent endogenous inhibitor of CPT-I. It is
generated from acetyl-CoA by ACCs. MCA is utilized by fatty
acid synthase as a substrate for fatty acid synthesis or is degraded
9,10
by the enzyme malonyl-CoA decarboxylase (EC 4.1.1.9). We
recently reported the identification and activity of the first-
1
1
,
†
†
†
generation, small-molecule MCD inhibitors. As expected,
pharmacological inhibition of MCD significantly increased
malonyl-CoA levels and shifted the energy production from fatty
acid oxidation to glucose oxidation in ex vivo experiments with
isolated working rat hearts and in vivo experiments in a pig
Jie-Fei Cheng,* Yujin Huang, Richard Penuliar,
†
†
†
Masahiro Nishimoto, Larry Liu, Thomas Arrhenius,
Guang Yang, Eoin O’Leary, Miguel Barbosa, Rick Barr,
Jason R. B. Dyck, Gary D. Lopaschuk, and
Alex M. Nadzan
‡
‡
‡
§
§
§
†
1
2
demand induced ischemia model. On the basis of these first-
generation MCD inhibitors, we have successfully developed
Departments of Chemistry and DiscoVery Biology,
Chugai Pharma USA, LLC., 6275 Nancy Ridge DriVe,
San Diego, California 92121, and Metabolic Modulator Research
Ltd. (MMRL), 2020 Research Transition Facility, UniVersity of
Alberta, Edmonton, Alberta, Canada
11
a novel class of potent MCD inhibitors with excellent PK and
ADME properties. Compound 5 (CBM-301940) potently stimu-
lates glucose oxidation in isolated working rat hearts and
improved cardiac efficiency and function in a severe global
ischemic/reperfusion rat heart model.
ReceiVed April 28, 2006
The synthesis of isoxazoline-based MCD inhibitors is depicted
in Scheme 1. Hexafluoro-2-propanol-containing dipolarophile,
1,1,1-trifluoro-2-trifluoromethylbut-3-en-2-ol, was prepared from
hexafluoroacetone (gas) and Grignard reagents according to the
Abstract: Discovery of 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-
yl)-4,5-dihydroisoxazole-3-carboxamides as a new class of malonyl-
coenzyme A decarboxylase (MCD) inhibitors is described. tert-Butyl
3-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-4,5-dihydroisoxazole-
13
literature procedure. Cycloaddition of commercially available
3-carboxamido)butanoate (5, CBM-301940) exhibited excellent potency
chlorooximidate 1 with this dipolarophile, in the presence of
triethylamine, afforded the key isoxazoline intermediate (2). The
reaction was performed by slow addition of triethylamine in
THF, using a syringe pump, to a solution of chlorooximidoac-
etate and 1,1,1-trifluoro-2-trifluoromethylbut-3-en-2-ol in THF
at room temperature. Saponification of the isoxazoline ester 2,
followed by coupling with appropriate amines, afforded the
desired isoxazoline derivatives 4 in moderate to good yields.
and in vivo PK/ADME properties. It is the most powerful stimulant of
glucose oxidation reported to date in isolated working rat hearts.
Compound 5 improved the cardiac efficiency and function in a rat heart
global ischemia/reperfusion model, suggesting MCD inhibitors may
be useful for the treatment of ischemic heart diseases.
A growing body of evidence points to the therapeutic value
1
of reducing fatty acid metabolism for ischemic heart diseases.
Fatty acid oxidation was dominated or enhanced in the hearts
of human patients and in animal models of diabetes (type I or
The synthesis of optically pure diasteromers of 5 (5c-f) is
outlined in Scheme 2. Starting from the diastereoisomeric 5a,
which was prepared from optically pure (S)-tert-butyl â-ami-
nobutarate and the racemic 3-isoxazoline carboxylic acid 2, two
diastereoisomeric Mosher esters (6a and 6b) were obtained by
reacting 5a with (S)-(+)-R-methoxy-R-trifluoromethylpheny-
lacetyl chloride. The two diastereomeric Mosher esters could
be separated by column chromatography and exhibited distinct
2
II) and ischemic heart disease (e.g., angina pectoris). As a
consequence of the interdependence of fatty acid oxidation and
3
glucose oxidation (Randle cycle ), enhancing fatty acid oxidation
would reduce glucose utilization and further complicate the
symptoms or worsen the disease. Reducing fatty acid utilization,
on the other hand, would promote the shift of energy production
from fatty acid to glucose and lead to the improvement of
cardiac efficacy and function. In the cellular system, oxidation
1
19
13
chemical shifts and/or coupling constants in H, F, and
C
NMR spectra in the isoxazoline and ester regions. Hydrolysis
of these two compounds provided optically pure diastereomers
of long-chain fatty acids is controlled by carnitine palmitoyl-
transferases4 (CPT-I and CPT-II). Inhibitors of CPT-I or
5
(
5
c and 5d. Similarly, two other optically pure diastereoisomers
5e and 5f) were obtained via sequential reactions starting from
b, which in turn was prepared from optically pure (R)-tert-
â-oxidation enzymes are expected to decrease fatty acid
oxidation rates and accelerate glucose oxidation. Indeed, a
diverse group of antianginal drugs such as perhexiline (2-(2,2-
dicyclohexylethyl)piperidine) and amiodarone (((2-butylbenzo-
furan-3-yl)-[4-(2-diethylaminoethoxy)-3,5-diiodophenyl]meth-
butyl â-aminobutyrate.
The absolute configuration of 5c was assigned through a
combination of chemical reaction and X-ray crystallographic
analysis of intermediate Mosher ester (7a, Scheme 2 and Figure
5
anone) are believed to act as CPT-I inhibitors. The partial fatty
acid oxidation inhibitor, ranolazine (N-(2,6-dimethylphenyl)-2-
1
4
[4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]piperazin-1-yl]ac-
1). Mosher ester 7a was prepared according to Scheme 1 and
subsequently converted into 5c, which is identical in all aspects
of spectroscopic data, including optical rotation, to the com-
pound prepared from 5a. Therefore, the absolute configuration
of 5c was determined as S,R. The diasteroisomer 5d was then
assigned to have S configuration at the C5 position of the
isoxazoline ring. Accordingly, the absolute stereochemistry of
two remaining diasteroisomers prepared from the R amino acid
etamide), has been approved recently by FDA as a new class
6
of antianginal drug. Another drug, trimetazidine (1-[(2,3,4-
trimethoxyphenyl)methyl]piperazine), used for chronic angina
pectoris, is a potent inhibitor of 3-ketoacyl coenzyme A thiolase,
a key enzyme in the â-oxidation spiral.7
*
To whom correspondence should be addressed. Present address:
Tanabe Research Laboratories USA, Inc., 4540 Towne Centre Court, San
Diego, CA 92121. Phone: (858)-622-7029. Fax: (858)-558-9383. E-mail:
jcheng@trlusa.com.
a
Abbreviations: MCA, malonyl-coenzyme A; CoA, coenzyme A; MCD,
†
Department of Chemistry, Chugai Pharma USA, LLC.
Department of Discovery Biology, Chugai Pharma USA, LLC.
University of Alberta.
malonyl-coenzyme A decarboxylase; PK, pharmacokinetic; ADME, absorp-
tion, distribution, metabolism, and excretion; CPT, carnitine palmitoyl-
transferase; ACC, acetyl-coenzyme A carboxylase; GOX, glucose oxidation.
‡
§
1
0.1021/jm0605029 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/17/2006

4
056 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14
Letters
Scheme 1. Synthesis of 5-(1,1,1,3,3,3-Hexafluoro-2-hydroxy-
Table 1. Isoxazoline-Based MCD Inhibitors (I)
propan-2-yl)-4,5-dihydroisoxazole-3-carboxamidesa
a
IC50 (nM)a
Reagents and conditions: (a) Et3N (1.1 equiv), 1,1,1-trifluoro-2-
compd
R1
R2
trifluoromethylbut-3-en-2-ol; (b) NaOH aq, ethanol; (c) BOP, R1R2NH, 4-N-
methylmorpholine, DMF.
i
i
i
4a
Bu-
Bu-
Bu-
H
801
676
137
489
60
28
28
1767
463
421
31
17
7
9
113
15
30
45
37
5
4b
Me
i
Scheme 2. Preparation of Stereoisomers of Compound 5a
4c
Bu
4
4
4
4
4
4
4
4
4
4
4
4
4
d
e
f
g
h
i
j
k
l
m
n
o
p
tBuCH2CH2-
2-hepatyl-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6-methyl-2-heptyl-
tBuOCH2CH2CH2-
EtO2CCH2-
EtO2CCH2CH2-
EtO2CCH2CH2CH2-
tBuO2CCH2CH2-
i
Pr2NCOCH2CH2-
CH3(Et)2CO2CCH2CH2-
i
CH3( Bu)2CO2CCH2CH2-
S-tBuO2CCH(Bn)-
i
S-tBuO2CCH2CH( Bu)-
i
a
4q
(()-tBuO CCH CH( Bu)-
Reagents and conditions: (a) (S)-(+)-R-methoxy-R-trifluoromethylphe-
2
2
i
4r
4s
4t
R-tBuO2CCH2CH( Bu)-
nylacetyl chloride [(S)-MTPA-Cl], Et3N, DMAP, THF; (b) NaOH aq,
ethanol; (c) (S)-tert-butyl â-aminobutyrate, EDAC, DMAP, DCM, room
temp.
i
(()-Me( Bu)2CO2CCH2CH(Me)-
S-CH3(Et)2CO2CCH2CH(Me)-
a
Data are reported as the mean of n g 3 determinations. SD was
generally (20% of the average.
Table 2. Isoxazoline-Based MCD Inhibitors (II)
compd
A
B
IC50 (nM)a
5
RS
S
R
S
S
R
R
RS
RS
RS
S
R
R
23
7
10
136
5
Figure 1. ORTEP representation of the X-ray crystal structure of 7a.
5
5
5
a
b
c
ester was assigned by comparing the optical rotations and
characteristic NMR chemical shifts of Mosher ester intermedi-
ates.
5d
5
5
e
f
8
168
S
MCD inhibitors were tested for their ability to inhibit a soluble
maltose binding protein fused human malonyl-coenzyme A
decarboxylase as described previously.11,15 The IC50 values of
the synthesized compounds are tabulated in Tables 1 and 2.
The most potent compounds were further profiled in terms of
in vitro pharmaceutical properties (solubility, Caco-2 perme-
ability, rat and human metabolic stability, data not shown) and
in vivo PK/ADME properties. Selected compounds were
examined for their ability to stimulate glucose oxidation in
isolated working rat hearts. These results are summarized in
Table 3.
a
Data are reported as the mean of n g 3 determinations. SD was
generally (20% of the average.
Table 3. MCD Inhibitors and Glucose Oxidation Rates
compd
DMSO
IC50 (nM)
GOX rate (%)a
1
4
4
4
c
k
e
137
31
60
28
7
15
28
30
23
2.11
4.54
0.80
1.26
5.01
3.24
5.42
4.28
4f
5
4
4
4q
5
a
p
g
As summarized below, several key modifications provided
insight into the general SAR of this series. Although disubsti-
tuted (tertiary) amides with small aliphatic moieties such as 4b
b
7.32, 3.07
1.77
2.01
c
ranolazine HCl
(IC50 ) 676 nM) and 4c (IC50 ) 137 nM) are well tolerated,
trimetazidined
the more potent MCD inhibitors proved to be appropriately
monosubstituted amides (e.g., 4e and 4f). In general, increasing
hydrophobicity at the terminus of the side chain increased the
in vitro enzyme inhibitory potency. For example, tert-butyl ester
a
GOX rates were calculated as a ratio of test compound (10 µM) to
b
c
DMSO (0.05%) control (n ) 8 hearts). At 1 µM test concentration. See
ref 6a. d See ref 7.
4
k (IC50 ) 31 nM), diisopropylamide 4l (IC50 ) 17 nM) and
butyl function led to the less potent carboxylic acid (data not
shown), indicating that a hydrophobic group is indeed required
for the higher activity.
Introduction of a small alkyl group near the amide nitrogen
atom is well tolerated and beneficial. An isobutyl group (e.g.,
4p and 4q) is apparently better than a benzyl function (4o).
Introduction of a methyl group on the amine side chain led to
the discovery of 5, which contains a tert-butyl ester at the
bulkier ester compounds 4m and 4n (IC50 ) 7 and 9 nM)
exhibited higher potency than the corresponding ethyl ester
compounds 4i (IC50 ) 463 nM). The compound possessing a
terminal tert-butyl ether group (4g, IC50 ) 28 nM) was as potent
as the corresponding tert-butyl ester 4k. However, 4k exhibited
a better PK profile than the ether 4g (data not shown), perhaps
owing, in part, to the improved solubility. Removal of the tert-

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 14 4057
Table 4. Pharmacokinetic Parameters for MCD Inhibitor 5a
Through a process of structural optimization, an isoxazoline-
hexafluoro-2-propanol analogue, 5, was identified as a lead
MCD inhibitor. Compound 5 demonstrated low nanomolar
MCD inhibitory activity and a 7-fold increase at 10 µM or a
3-fold increase at 1 µM in glucose oxidation rates in the isolated
working hearts. Compound 5 also demonstrated cardioprotective
activity in a global ischemia-reperfusion rat model. In rats, 5
showed a greater than 70% oral bioavailability and an excellent
terminal half-life. The combination of high inhibitory potency,
excellent PK profile, potent glucose oxidation stimulating
activity, and in vivo efficacy in an animal model of disease
may render 5 as a valuable pharmacological tool in elucidating
the roles of MCD in cell signaling pathways and the potential
for usage in the treatment of ischemic heart disease and other
diseases that can be ameliorated by modulation of glucose and
fatty acid metabolism.
t
1/2, iv
(h)
CL
T
max, po
C
max, po
V
ss
F
1
(ng mL , po) (mL kg-1) (%)
-1
compd
(mL h- kg-1
)
(h)
5
2.3
915
0.5
2683
2193
74
a
After iv or oral dose of 10 mg/kg in Sprague-Dawley rats. Bioavail-
ability (F) was calculated as the ratio of dose-normalized po to iv AUCs
for the same time frame. Clearance (CL) is the rate at which a given amount
of plasma is totally cleared of unbound compound. Volume of distribution
(Vss) is an approximation of the volume that the compound would occupy
at steady state. Oral dosing vehicle was 80% PG/20% EtOH.
terminus (Table 2). Compound 5 is as potent as the parent 4k
or the isobutyl substituted analogue 4q. The chirality of the side
chain portion does not seem to be a determinant. The R and S
diastereoisomers 5a and 5b exhibited only a 2- to 3-fold increase
in MCD inhibitory activitiy compared to the racemic parent 5
(Table 2). However, a more profound influence of chirality on
activity was evidenced by a greater than 20-fold increase in
activity of the isoxazolines with R configuration at the C5
position of the isoxazoline ring vs their S counterparts (5c vs
Acknowledgment. We thank Dr. Peter Simms, Cynthia
Jefferies, and Aixia Sun for their assistance with HPLC and
MS analysis.
5
d, 5e vs 5f).
Supporting Information Available: Experimental procedures
and characterization of compounds, HRMS data for listed com-
pounds, and X-ray crystallographic data for 7a. This material is
available free of charge via the Internet at http://pubs.acs.org.
As described previously, MCD inhibitors cause an elevation
of malonyl-CoA levels, an increase of glucose oxidation rate,
and a decrease in fatty acid oxidation rates in isolated working
11,12
rat hearts.
A number of the isoxazoline-based MCD inhibi-
tors were selected on the basis of their favorable in vitro
properties, especially in vitro potency, solubility, and Caco-2
permeability, and tested for their ability to stimulate glucose
oxidation (Table 3).16 A clear correlation of in vitro potency
with glucose oxidation rate cannot be established probably
because of the differences in solubility and permeability among
the compounds tested. In general, however, the more potent
compounds exhibited a greater enhancement in glucose oxida-
tion rate. Compounds 4k, 5a, and the tert-butyl ether 4g caused
a 4- to 5-fold increase in glucose oxidation at 10 µM vs the
DMSO control. Compound 5 was found to be the most potent
metabolic modulator reported to date, demonstrating a 732%
increase in glucose oxidation rate when tested at 10 µM. Even
at a concentration as low as 1 µM, 5 accelerated the glucose
oxidation rate by more than 3-fold. The stimulation of glucose
oxidation by 5 is significantly more effective than known
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1
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