Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog re-design

Article abstract of DOI:10.1016/j.bmcl.2007.08.004

An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.

Full text of DOI:10.1016/j.bmcl.2007.08.004

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5567–5572
Pyrazole inhibitors of HMG-CoA reductase: An attempt
to dramatically reduce synthetic complexity through
minimal analog re-design
Scott D. Larsen,* Toni-Jo Poel, Kevin J. Filipski, Jeffrey T. Kohrt,
Jeffrey A. Pfefferkorn, Roderick J. Sorenson, Bradley D. Tait, Valerie Askew,
Lisa Dillon, Jeffrey C. Hanselman, Gina H. Lu, Andrew Robertson,
Catherine Sekerke, Mark C. Kowala and Bruce J. Auerbach
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 11 July 2007; revised 30 July 2007; accepted 1 August 2007
Available online 11 August 2007
Abstract—An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was
recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this
obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core
via an oxygen linker (‘oxypyrazoles’). This minor change reduced the total number of synthetic steps from 14 to 7. Although the
resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further devel-
opment. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be
responsible for the poor in vivo activity.
Ó 2007 Elsevier Ltd. All rights reserved.
Hydroxymethylglutaryl-Coenzyme
A
(HMG-CoA)
ists a need for new statins that are better tolerated at
higher doses and by physically active individuals.
reductase catalyzes the rate-limiting step in cholesterol
biosynthesis. Inhibitors of this enzyme (statins, e.g.,
atorvastatin (1) and rosuvastatin (2)) are highly effective
therapeutic agents for the treatment of hypercholesterol-
emia and have become the standard of care in the man-
agement and prevention of coronary heart disease.1
Recent data from several large clinical trials suggest that
more aggressive LDL-lowering beyond current target
guidelines will have additional benefits2; however,
achieving these reductions with marketed agents re-
quires higher doses or combination therapy. There is
now substantial evidence that elevated doses of statins
are associated with mild to moderate myalgia,3 a type
of muscle pain or weakness that negatively impacts
quality of life and can erode patient compliance. Low
tolerance to statin therapy is particularly evident in indi-
viduals who exercise vigorously.4 Consequently there ex-
The mechanism(s) responsible for statin-induced myal-
gia remain unclear, but likely entail disruption of mev-
alonate metabolism in muscle.5 Myalgia can be
exacerbated by factors that inadvertently increase
blood levels of the statin or render patients more sen-
sitive to treatment, for example, drug–drug interactions
or genetic polymorphisms.6 A logical strategy for
avoiding statin biochemical effects in muscle is to de-
sign agents that are more effective in hepatic tissue
than non-hepatic tissue. At the cellular level, this has
been successfully achieved through simple reduction
in statin lipophilicity.7 Hydrophilic statins do not pas-
sively diffuse well into cells, requiring some level of ac-
tive transport to achieve good efficacy. Hepatic cells
possess organic anion transporting polypeptides (OAT-
Ps), for which statins are known to be viable sub-
strates.8 Muscle cells, on the other hand, are devoid
of OATPs, so they should be less susceptible to the ef-
fects of hydrophilic statins, an attribute that has been
confirmed experimentally.9
Keywords: HMG-CoA reductase; Cholesterol; Atherosclerosis; Statin.
*
Corresponding author. Tel.: +1 734 323 1187; e-mail: sdlarsen
@umich.edu
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.08.004

5568
S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5567–5572
We recently reported the discovery of a potent and
hepatoselective new class of pyrazole-based statins 3
(Fig. 1).10 Extensive SAR work led to the eventual selec-
tion of PF-3052334 (3f, Table 1) for progression into ad-
vanced pre-clinical studies. Despite their highly
favorable PK profiles and in vivo efficacy, development
of this class of compounds was impeded by a lengthy
and challenging synthetic route (total of 14 steps).10 It
occurred to us that the synthesis of such pyrazole-based
statins could be simplified by the replacement of the
methylene unit linking the dihydroxy acid sidechain to
the heterocyclic core with an ether oxygen. It was antic-
ipated that the resulting ‘oxypyrazoles’ 4 would main-
tain most, if not all, of the closely related pyrazoles’
biological activity due to the minimal structural change
and to favorable literature precedent for ether-linked
statins with good biological activity.11
resulting benzyl ester 8, carboxylic acid 9 was converted
to various amide analogs 10 using EDCI-mediated cou-
pling conditions. Final analogs 4 were obtained as so-
dium salts following removal of the diol protecting
group with methanolic HCl and subsequent saponifica-
tion of the tert-butyl ester. The total number of linear
steps in this sequence is seven, a significant improvement
over the 13 linear steps required for the corresponding
pyrazole analogs 3.10 Furthermore, the sidechain could
be installed using the commercially available alcohol
11, whereas the pyrazole synthesis requires conversion
of 11 to the corresponding aldehyde. Thus we were suc-
cessful in dramatically facilitating the preparation of
analogs in the pyrazole series by altering the design of
the sidechain linker and truncating the overall synthesis.
New analogs were evaluated in a rat liver microsomal
assay for HMG-CoA reductase activity, followed by
two rat cellular assays for inhibition of cholesterol syn-
thesis.10 Both hepatic and non-hepatic (L6 myocyte)
cells were employed to provide an estimate of the ability
of the compounds to inhibit cholesterol synthesis selec-
tively in the liver. Results are summarized in Table 1.
Data for rosuvastatin and selected pyrazoles 3 are in-
cluded for comparison.
We planned to limit our SAR investigation of the oxy-
pyrazoles to variations of the carboxamide substituent,
as it had been well established that the dihydroxyacid
sidechain, the iso-propyl group, and the 4-fluorophenyl
group of 4 are optimal in heterocycle-based statins.
The preparation of oxypyrazole carboxamides 4 is sum-
marized in Scheme 1. Deprotonation of ester 5 with
LDA, followed by acylation with dibenzyl oxalate, pro-
vided the keto diester 6. Condensation of 6 with 4-fluor-
ophenyl hydrazine at elevated temperature then
regioselectively afforded the desired hydroxypyrazole es-
ter 7 in good yield. The key attachment of the dihydr-
oxyacid sidechain was accomplished under Mitsunobu
conditions, using the commercially available ketal-pro-
tected trihydroxy ester 11. After hydrogenolysis of the
Compounds were selected for synthesis based largely on
the SAR of the related pyrazole series.10 Thus, emphasis
was placed on substituted benzyl amides and alkyl
amides that had performed well in that series. The first
prototype oxypyrazole prepared was simple benzyl
amide 4a, which did not meet our criteria for hepatose-
lectivity [L6 myocyte IC50 > 1000 nM and/or (L6 IC50/
hepatocyte IC50) > 1000]. To our surprise, simple N-
methylation of the benzyl amide (to give 4b) effected a
significant improvement in hepatocyte activity. This
trend proved to be fairly general, as illustrated with
the following compound pairs: 4c/4d, 4j/4u, 4m/4r. In
some cases, N-methylation also attenuated the activity
in myocytes, dramatically improving the hepatoselectiv-
ity (e.g., 4b). A quick survey of substituents at the 2-, 3-,
and 4-positions of the primary benzyl amide (4f–4n) re-
vealed that 3-substitution produced the best level of
activity in the microsomal and/or hepatocyte assays,
and that simple methyl proved more effective than meth-
oxy or halogen in hepatocytes. Among the other substit-
uents examined at that position, methoxymethyl (4jj)
also possessed superior hepatocyte activity.
O
O
OH
OH
HO
HO
HO
HO
N
F
N
F
N
O
N
NH
SO2CH3
2
1
O
Within a series of 3-substituted N-methylbenzyl amides
(4o–4u), the nature of the substitution did not seem to
significantly impact the hepatocyte activity. In this ser-
ies, halogen appeared to be among the best, so it was ex-
plored further with analogs 4v–4x. Homologation of the
unsubstituted benzyl amide (4z), a-methyl substitution
(4y), and increasing the size of the N-methyl group to
ethyl (4aa) all were detrimental to microsomal activity
relative to prototypes 4a and 4b. Alkyl amides in general
performed poorly (three examples shown: 4bb, 4cc, 4hh)
except for selected tertiary alkyl amides (e.g., N-methyl
cyclohexylmethyl analog 4dd). Conformational restric-
tion of the benzyl amide was investigated with analogs
4ee–4gg. (R)-3-Phenylpiperidine analog 4gg was of par-
O
OH
OH
HO
HO
HO
HO
N
O
F
F
N
N
O
N
O
N
N
R2
R2
R1
R1
3
4
Figure 1. Atorvastatin (1), rosuvastatin (2), and pyrazole (3) and
oxypyrazole (4) HMG-CoA reductase inhibitors.

S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5567–5572
Table 1. In vitro biological activity of oxypyrazoles 4 and selected pyrazoles 3
5569
Compound
R1
R2
HMGRa IC50
Hepatob IC50
L6 myoc IC50
4a
4b
4c
PhCH2
PhCH2
H
3.8
5.2
2.0
14
37
15
4.9
17
12
16
22
6.7
5.4
9.5
16
43
14
8.3
37
31
21
5.7
8.7
18
21
15
14
17
76
6.2
14
10
4.8
47
25
31
14
880
Me
H
1.1
19
6720
120
2,3-DiF–PhCH2
2,3-DiF–PhCH2
4-Me–PhCH2
4-Me–PhCH2
3-Me–PhCH2
2-Me–PhCH2
4-MeO–PhCH2
3-MeO–PhCH2
2-MeO–PhCH2
4-Cl–PhCH2
3-Cl–PhCH2
2-Cl–PhCH2
3-EtO–PhCH2
3,5-DiMeO–PhCH2
3-F–PhCH2
4d
4e
Me
Me
H
2.8
1.2
1.8
0.99
0.88
37
860
1250
2110
280
4f
4g
4h
4i
H
H
2850
nd
H
4j
H
8.4
83
8750
nd
4k
4l
H
H
44
nd
nd
4m
4n
4o
4p
4q
4r
H
9.9
76
H
8450
3550
nd
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
2.8
7.1
1.9
1.8
2.5
12
2470
2120
18500
nd
3-Cl–PhCH2
3-Me–PhCH2
3-F3C–PhCH2
3-MeO–PhCH2
3,4-DiF–PhCH2
2-F–PhCH2
4s
4t
4u
4v
1.6
8.0
3.2
3.8
11
9460
4570
11600
2800
nd
4w
4x
4y
4z
4-F–PhCH2
(R)-PhCH(CH3)
PhCH2CH2
PhCH2
14
760
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
4ii
4jj
Et
H
4.7
56
2660
nd
c-C6H11–CH2
n-Bu
H
Me
39
nd
c-C6H11–CH2
2-Ph-Pyrrolidine
Tetrahydroisoquinoline
(R)-3-Ph-Piperidine
Piperidine
1.3
8
2510
4340
1720
1110
32200
nd
2.5
1.5
3.8
7.5
1.1
2-Pyr-CH2
3-(MeOCH2)–PhCH2
H
H
3600
Rosuvastatin
2.1
6.2
2.5
4.1
2.1
0.23
0.31
1.1
210
3b
3f
PhCH2
Me
H
2870
800
4-Me–PhCH2
3-F–PhCH2
(R)-3-Ph–Piperidine
3q
3gg
Me
0.16
0.28
1900
310
nd, not determined.
a Inhibition of HMG-CoA reductase in rat liver microsomes (nM).
b Inhibition of cholesterol synthesis in rat hepatocytes (nM).
c Inhibition of cholesterol synthesis in L6 myocytes (nM).
ticular interest, as the corresponding pyrazole analog
3gg was among the most active within that series. Final-
ly, an attempt to replace the phenyl ring of the benzyl
amide with a heterocycle (4ii) was detrimental to micro-
somal activity.
10 mg/kg po dose of the test compound, followed by a
bolus of sodium 14C-acetate at one of three time points:
2, 3 or 4 h after the test compound dosing. After an
ensuing 2-h time period, the amount of label incorpo-
rated into plasma cholesterol was determined. Results
are summarized in Table 2 as percent change in label
incorporation relative to vehicle. Measuring cholesterol
synthetic rate over time provides an estimate of each
compound’s duration of action after an acute dose,
which we considered a good predictor of chronic
LDL-lowering activity. Among marketed statins, long
half-lives in vivo are associated with the greatest degree
of chronic efficacy.12 Data for rosuvastatin and selected
pyrazoles are provided in the table for comparison.
A direct comparison of oxypyrazoles 4b, 4f, 4q, and 4gg
with the corresponding pyrazoles 3b, 3f, 3q, and 3gg
indicates that overall the oxypyrazoles, while clearly
being potent inhibitors of HMG-CoA reductase, were
nevertheless somewhat less active in both the micro-
somal and hepatocyte assays relative to their pyrazole
counterparts.
Selected compounds were tested in vivo for their ability
to acutely inhibit cholesterol synthesis in male Syrian
Golden hamsters.10 Animals were administered a single
It is immediately apparent from Table 2 that the oxypy-
razoles were distinctly less active in vivo than their pyr-

5570
S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5567–5572
OEt
O
OH
N
OEt
O
i, ii
iii
F
O
O
N
O
OBn
5
7
OBn
6
O
O
OtBu
OtBu
O
O
O
OtBu
O
O
O
O
O
O
11
HO
v
F
F
N
N
N
iv
N
O
O
OBn
8
OH
9
O
O
OtBu
ONa
O
HO
O
HO
O
O
vi
vii, viii
F
F
N
N
N
N
O
O
N
N
R2
R2
R1
R1
10
4
Scheme 1. Reagents and conditions: (i) 1.1 equiv LDA, THF, ꢀ78 °C; (ii) dibenzyl oxalate; (iii) 4-F–Ph–NHNH2ÆHCl, AcOH/toluene, 50–90 °C, 32–
37% overall for steps i–iii; (iv) Ph3P, DEAD, THF, ꢀ5 °C ! rt, 88%; (v) H2, Pd/C, MeOH, rt, >95%; (vi) R1R2NH, EDC, HOBt, DCM, 18 h, rt,
>88%; (vii) HCl, MeOH, rt, 82–90%; (viii) NaOH, MeOH, rt, 75–90%. Detailed experimental procedures are provided in Ref. 16.
Table 2. In vivo biological activity of oxypyrazoles 4 and selected pyrazoles 3
Compound
R1
R2
HAICSa (2–4 h)
HAICS (3–5 h)
HAICS (4–6 h)
4a
4b
4f
PhCH2
PhCH2
H
+41%
+26%
+9%
Me
H
ꢀ49%
ꢀ30%
4-Me–PhCH2
2-Me–PhCH2
3-MeO–PhCH2
3-F–PhCH2
4h
4j
H
+39%
+37%
ꢀ1%
H
4q
4r
Me
Me
Me
Me
Me
Me
Me
ꢀ41%
3-Cl–PhCH2
3-MeO–PhCH2
3,4-DiF–PhCH2
2-F–PhCH2
0%
4u
4v
+53%
ꢀ5%
ꢀ4%
4w
4x
4dd
4gg
4jj
4-F–PhCH2
c-C6H11
+91%
+23%
(R)-3-Ph-Piperidine
3-(MeOCH2)–PhCH2
ꢀ15%
H
ꢀ6%
Rosuvastatin
ꢀ76%
ꢀ61%
ꢀ74%
ꢀ66%
ꢀ78%
ꢀ46%
ꢀ16%
ꢀ15%
ꢀ12%
3b
3f
PhCH2
Me
H
4-Me–PhCH2
3-F–PhCH2
(R)-3-Ph-Piperidine
3q
3gg
Me
ꢀ57%
a Acute inhibition of cholesterol synthesis in hamsters following a single oral dose (10 mg/kg) during the indicated 2-h period (2–4 h) post-dose.
azole counterparts. Each of the four pyrazole compara-
tor examples in the table maintained their ability to in-
hibit cholesterol synthesis in vivo for at least 5 h post-
dose. On the other hand, none of the oxypyrazoles were
active beyond 4 h post-dose. Short term activity in vivo
was observed with several oxypyrazole analogs (2–4 h),
but none of these could maintain efficacy past 4 h. It is
interesting to note the apparent increases in cholesterol
synthetic rate at some of the longer timepoints. These
data suggest the compounds were working acutely and

S. D. Larsen et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5567–5572
5571
this class of compounds in vivo, no detailed PK studies
were undertaken to confirm this hypothesis.
In summary, we were successful in designing a greatly
simplified synthesis of pyrazole-centered statins by
incorporating a minor change in the sidechain linkage.
While the resulting oxypyrazoles retained much of the
pyrazoles’ in vitro activity, they were distinctly inferior
in vivo, possibly due to a greater susceptibility to active
efflux from the gut and/or liver.
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