Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series

Article abstract of DOI:10.1016/j.bmcl.2011.12.002

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

Full text of DOI:10.1016/j.bmcl.2011.12.002

Bioorganic & Medicinal Chemistry Letters 22 (2012) 980–984
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD)
inhibitors in a bispyrrolidine series
Nicolas Lachance a, , Yves Gareau a, Sébastien Guiral b, Zheng Huang b, Elise Isabel a, Jean-Philippe Leclerc a,
⇑
Serge Léger a, Evelyn Martins a, Christian Nadeau c, Renata M. Oballa a, Stéphane G. Ouellet c,
David A. Powell a, Yeeman K. Ramtohul a, Geoffrey K. Tranmer a, Thao Trinh c, Hao Wang b, Lei Zhang b
a Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1
b Department of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1
c Department of Basic Pharmaceutical Sciences, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Hwy, Kirkland, Quebec, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treat-
ment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse
events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been
focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to
the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These
compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity
in a mouse pharmacodynamic model.
Received 31 October 2011
Revised 30 November 2011
Accepted 1 December 2011
Available online 8 December 2011
Keywords:
Stearoyl-CoA desaturase inhibitors
SCD inhibitors
Ó 2011 Elsevier Ltd. All rights reserved.
Desaturation index
Liver-targeted
MK-8245
Elevated stearoyl-CoA desaturase (SCD) activity has been linked
to a number of metabolic disorders including obesity and type II
diabetes, which continue to expand at epidemic rates.1 The SCD en-
zyme exists as two isoforms in humans (SCD1 and SCD5) and four
in rodents (SCD1-4), with SCD1 being the isoform which is pre-
dominantly expressed in liver (target organ for efficacy). It has
been reported that adverse events (AEs),2 such as partial eye clo-
sure and progressive alopecia, appear in mice after ꢀ7 days of
treatment with systemically-distributed SCD inhibitors. These
AEs are likely due to the depletion of SCD-derived lubricating lipids
in skin and eye, and it was initially hypothesized that liver-tar-
geted SCD inhibitors should circumvent these issues.3
The initial strategy employed in the design of liver-selective
compounds centers on exploring the addition of polar acidic moi-
eties which are recognized by organic anionic transporters (OAT-
Ps),4 such as tetrazoles or carboxylic acids, on SCD inhibitors to
obtain the desired in vivo properties: a high liver concentration
(target organ for efficacy) and a low systemic concentration to
minimize exposures in off-target tissues and cells associated with
adverse events (skin and eye).
with an enzymatic potency (IC50) against the rat SCD of 3 nM.5 This
compound possesses good in vivo potency in a mouse liver phar-
macodynamic model (mLPD, ED50 ꢀ1 mg/kg).6 Moreover, MK-
8245 demonstrated a therapeutic window for liver-lipid efficacy
in the absence of AEs after 4 weeks of chronic dosing in mice.5 Fol-
lowing the discovery of MK-8245, our research efforts continued
on the identification of structurally diverse liver-targeted SCD
inhibitors for the selection of a back-up compound to our lead
MK-8245 to support the development of SCD inhibitors in preclin-
ical species and eventually in humans.7
In vitro studies have demonstrated that the liver-targeted tissue
distribution profile of MK-8245 is likely a result of substrate recog-
nition by organic anionic transporter proteins (OATPs) which are
highly expressed in hepatocytes.4,5 An important feature in the
structure of MK-8245 is the tetrazole acetic acid moiety, which is
the key functionality for OATP recognition. In search for new struc-
tural classes, we intentionally kept this group in place for active
transporter recognition and modified other parts of the molecule.
We envisioned that replacement of the piperidine core in MK-
8245, which is commonly found in many SCD-inhibitors,2a,8 with
linkers such as a bicyclic heterocycles (A–B) may provide a distinct
and structurally diverse series of SCD1 inhibitors 1 (Fig. 1).9,10
In the absence of an SCD1 enzyme X-ray crystal structure, we
chose to proceed with a systematic SAR study to guide our optimi-
zation efforts. Initially, we turned our attention to the synthesis of
We recently disclosed MK-8245 (Fig. 1), a phenoxy piperidine
isoxazole derivative, as a potent and liver-selective SCD inhibitor
⇑
Corresponding author.
E-mail address: nicolas.lachance21@gmail.com (N. Lachance).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.002

N. Lachance et al. / Bioorg. Med. Chem. Lett. 22 (2012) 980–984
981
O
HO
N
N
N
N
N
O
F
Br
O
N
MK-8245 (Rat SCD IC50: 3 nM)
O
O
HO
N
N
HO
N
N
N
N
Bispyrrolidine
Cl
N
N
HetAr
N A - B N
N
N
O
N
R
F
1
2
Figure 1. MK-8245, core structure of heterocyclic linkers 1 and bispyrrolidine compound 2.
the bispyrrolidine linker 2 (Fig. 1) while keeping the remaining
structural elements of MK-8245 almost unchanged. The bromine
atom on the phenyl ring was substituted by a chlorine atom to sim-
plify the synthetic route (Scheme 1).
As depicted in Scheme 1, the construction of heterocyclic linker
counterparts 5 involved the Buchwald–Hartwig amination of aryl
bromide 4 with amino heterocycle 3 in the presence of a base
(NaOt-Bu) and a catalytic amount of Pd(OAc)2 and ( )-BINAP.9,11
The N-Boc protecting group was then cleaved under acidic condi-
tions with HCl or TFA to form the corresponding salt 5.
Having in hand a suitable collection of linkers 5 derived from
different heterocyclic linkers (A–B) 3, we next turned our attention
to join these molecules to the isoxazole tetrazole acetic acid moi-
ety. As illustrated in Scheme 2, the synthetic route consisted of a
stepwise construction of the tetrazole acetic acid group. To this
end, reaction of 3-bromoisoxazoline 6 with 5a under addition–
elimination conditions with Na2CO3 gave the corresponding prod-
uct 7.12 The isoxazoline 7 thus obtained was conveniently oxidized
to the desired isoxazole 8 with I2 in presence of imidazole.12 The
preparation of the tetrazole 9 was completed by dehydration of
amide 8 with TFAA to the corresponding nitrile followed by reac-
tion with NaN3 under slightly acidic conditions. Introduction of
the acetate ester group on the tetrazole 9 gave two regioisomers
10 and 11. It was observed that under Et3N and THF conditions, a
good ratio (>3:1) in favor of 10 could be obtained.13 Finally, hydro-
lysis of 10 with aqueous formic acid afforded 2.
We rapidly realized that the connection of a broad range of het-
erocyclic linkers 5 with the isoxazole aromatic core contained in
MK-8245 would require a repetitive tedious synthesis of the tetra-
zole acetic acid moiety, as well as the oxidation step of the isoxaz-
oline to the isoxazole aromatic ring for each analog. For synthetic
ease, we decided to explore the replacement of the isoxazole ring
with other five-membered heterocycles before evaluating other
heterocyclic linkers (A–B) contained in 5.
As reported in Scheme 3, a flexible route for the synthesis of thi-
azole 18 and thiadiazole 19 (Table 1) was developed through the
use of a highly functionalized intermediate 16. Compounds 18
and 19 were prepared via displacement of a bromo-heterocycle
16 with an appropriately substituted phenyl heterocyclic linker
5, followed by cleavage of the ester group under either basic or
acidic conditions. The versatile synthetic intermediate 16 was ac-
cessed through the elaboration of the tetrazole acetic acid group
from the nitrile 14 by employing similar conditions as described
for the isoxazoles 2 (Scheme 2). Following literature conditions,9
the nitrile intermediate 14 was prepared from the thiazole 12 or
the thiadiazole 13. In addition, employing this route for thiazole
18 and thiadiazole 19 represented an expedient method that also
allows the preparation of heterocycle targets 20–25 in only two
steps.
The SCD inhibitors prepared were tested against the SCD1 en-
zyme in an SCD-induced rat liver microsomal assay.14 Their cellu-
lar potencies were evaluated in a human hepatocellular carcinoma
General scheme to access heterocyclic linker intermediates (5)
a
+
N
A - B NH
H2N A - B N
BOC
Br
b or c
R
R
X
3
4
5
HX = HCl, TFA
Heterocyclic linkers (A-B) (3):
BOC
N
NH
NH
BOC
N
NH
BOC N
NH
3a
3b
3c
BOC
N
NH
BOC
N
BOC N
NH
3d
3e
3f
Scheme 1. Preparation of intermediates 5. Reagents and conditions: (a) Sealed tube: Pd(OAc)2, ( )-BINAP, NaOt-Bu, toluene, 115–120 °C for 16 h; (b) 2.0 M HCl in 1,4-
dioxane, rt for 2 h; (c) TFA, CH2Cl2, rt for 1 h.

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N. Lachance et al. / Bioorg. Med. Chem. Lett. 22 (2012) 980–984
Synthesis of bispyrrolidine isoxazole compound (2)
O
O
N
N
O
N
Cl
Cl
Cl
Cl
Cl
Cl
H2N
H2N
a
H2N
b
Br
+
H2N
Cl
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
N
N
N
N
N
N
6
5a
F
7
F
F
F
8
9
F
F
c,d
O
O
N
N
t-BuO
N
N
N
N
N
N
Cl
N
e
N
+
t-BuO
H
N
N
O
N
O
F
11: Minor
10: Major
f
HO
N
N
N
N
2
Scheme 2. Preparation of bispyrrolidine 2. Reagents and conditions: (a) Na2CO3, n-BuOH, 110 °C for 16 h; (b) I2, imidazole, toluene, reflux for 16 h; (c) TFAA, Et3N, THF, 0 °C to
rt for 1 h; (d) NaN3, NH4Cl, DMSO, 1,4-dioxane, 110 °C for 16 h; (e) t-butyl bromoacetate, Et3N, THF, 80 °C for 1 h; (f) 85–90% aq HCO2H, 100 °C for 1 h.
General route to heterocyclic compounds (18-25)
O
O
S
N
EtO
R1O
N
N
N
N
N
a,b
c,d
Br
H
N
N
N
N
N
N
NC
S
N
S
N
S
N
S
N
N
H
e
f or g
O
12
Br
Br
Br
Br
+
A
A
A
A
R1O
15
16: Major
14
A = CH, N
17: Minor
R1 = Et, t-Bu
H2N
S
N
O
N
h
i or j or k
HO
N
N
N
N
13
S
N
N
A - B N
A
R2
18-25
Scheme 3. Preparation of analogs in Tables 1 and 2. Reagents and conditions: (a) NH4OH, MeOH, THF, rt for 4 h; (b) TFAA, Et3N, THF, 0 °C to rt for 2 h; (c) Br2, NaOAc, concd
AcOH, rt for 3 h; (d) CuCN, t-butyl nitrite, MeCN, 0 °C to rt for 1 h; (e) Sealed tube: NaN3, ZnBr2, H2O, i-PrOH, 120 °C for 5–16 h; (f) (A = CH): ethyl bromoacetate or t-butyl
bromoacetate, Et3N, THF, 80 °C for 1 h; (g) (A = N): ethyl bromoacetate, CsCO3, DMF, 90 °C for 1 h; (h) 5, DBU or Hünig’s base, NMP, 120–130 °C for 20–30 min; (i) 1 N LiOH,
MeOH, THF, rt for 1 h; (j) TFA, CH2Cl2, rt for 4 h; (k) 85–90% aq HCO2H, 100 °C for 1 h.
line (HepG2) as the whole cell assay in which cells are devoid of ac-
tive OATPs.15 The ability to cross the cell membrane through active
transporters was assessed in a rat hepatocyte (Rat Hep) assay
which contains functional OATPs.5 The purpose was to qualita-
tively determine if an SCD inhibitor was actively transported into
hepatocytes (potent Rat Hep IC50) while maintaining poor cell per-
meability (poor HepG2 IC50) to avoid passive diffusion into off-
target cells.
As shown in Table 1 across the bispyrrolidine analogs 2, 18 and
19, the optimal heterocycle is the isoxazole ring, but the thiazole
ring is quite comparable.16 The isoxazoyl bispyrrolidine 2 displayed
a ꢀ400-fold potency shift between the microsomal enzyme assay
(Rat SCD) and the HepG2 cellular assay (IC50 = 9900 nM) but
desaturase), compound 2 displayed an IC50 of 27 nM compared to
1 nM for MK-8245.5 The bispyrrolidine linker 2 is slightly less po-
tent at inhibiting the other isoform found in human (hSCD5
IC50 = 242 nM).17 In addition, it is selective over two other desatur-
ase enzymes (delta-5 and delta-6 desaturases) present in human,
with IC50s >80 l
M in a whole cell assay.15
Before pursuing further SAR, we decided to evaluate the
in vivo potency of 2 in a mouse liver pharmacodynamic model
(mLPD).6 To support this model, the activity for the bispyrrolidine
2 was measured in a mouse SCD1 enzyme assay (IC50 = 18 nM)
which showed a similar potency compared to the rat SCD en-
zyme. Also, the dose selection was based on the pharmacokinetic
(PK) profile determined in C57BL6 mice following oral dosing at
10 mg/kg in 0.5% methocel as the vehicle. Under these conditions,
the bispyrrolidine 2 had a reasonable liver concentration of
improved to 8-fold in the rat hepatocyte cellular assay (IC50
=
198 nM), which suggests recognition by active transporters. Over-
all, the bispyrrolidine 2 showed 3 to 9-fold reduced in vitro potency
(Rat SCD, HepG2 and Rat Hep) when compared to MK-8245
(Table 1).
2.7 lM at a 6 h time-point (F = 24%, AUC0–6h = 2.1 lM h). Conse-
quently, a moderate dose (10 mg/kg) of 2 was enough to effi-
ciently suppress liver SCD activity in the mLPD assay (72%
The enzymatic potency against the human SCD enzyme was
also measured. In a human SCD1 enzyme assay (hSCD1) (delta-9
inhibition at a liver concentration of 14.8
point). In contrast, the more potent MK-8245 required a lower
lM of 2 at a 3 h time-

N. Lachance et al. / Bioorg. Med. Chem. Lett. 22 (2012) 980–984
983
Table 1
SAR on the heteroaromatic ring
X
HO
N
N
N
O
HetAr
Linker
N
F
a
Compound
HetAr-linker
X
IC50 (nM)
Rat SCD
3
HepG2
Rat Hep
MK-8245
Br
Cl
Cl
Cl
1070
68
N
N
N
N
O
N
N
O
N
2
24
34
59
9900
198
233
300
O
N
S
18
15,400
>10,000
N
S
19
N
N
N
a
IC50s are average of at least two independent titrations.
replacement for the isoxazole ring, we pursued further SAR explo-
ration through evaluation of a broad range of heterocyclic linkers
(A–B) (Table 2). The rapid preparation of these analogs 21–25 re-
lied on the convenient two steps coupling of phenyl heterocyclic
linkers 5 with the key thiazole intermediate 16 (Scheme 3).
The activities on the SCD-induced rat liver microsomal assay for
the heterocycles 21–25 prepared are reported in Table 2. Interest-
ingly, SCD inhibitory activity (HepG2 and Rat Hep) was slightly im-
proved with the piperazine tether 21. However, the spiro linkers
23–25 were intrinsically less potent. Having in hand two good
replacements for the piperidine core, namely the bispyrrolidine
and the piperazine, we turned our attention to the SAR on the phe-
nyl moiety in both series. Among the many substituents ex-
plored,18 we found that the phenyl ring substituted with an OCF3
group instead of the fluorine improved the in vitro potency of 20
when compared to 18 (Tables 1 and 2). However with compound
21, the current chlorine–fluorine substitution pattern on the phe-
nyl ring appeared optimal.18
Table 2
SAR on the heterocyclic linker
O
HO
N
N
Cl
N
S
N
N
Linker
R
Compound Linker
R
IC50 (nM)
Rat SCD HepG2
Rat Hep
113
20
OCF3
F
9
2450
4200
N
N
21
28
134
N
N
22
F
F
F
29
9140
176
103
For comparison to 2, PK profiles were measured for the thia-
zoles 20 and 21 in C57BL6 mice following a typical 10 mg/kg oral
N
N
dosing (20: F = 38%, AUC0–6h = 1.5
0.7 M h). Gratifyingly, the liver concentrations at a 6 h time-
point (20: 21.3 M; 21: 9.3 M) were significantly improved.
lM h; 21: F = 15%, AUC0–6h =
23
43
50,900
N
N
l
l
l
24
128
>100,000 506
>100,000 438
N
N
Evaluation of the bispyrrolidine 20 in the mLPD model showed
a 76% inhibition at a lower dose of 2 mg/kg with a liver exposure
of 23.2
l
M, whereas the piperazine 21 exhibited a 61% inhibition
M (total drug con-
25
F
36
N
N
at the same dose with a liver exposure of 7.7
l
centration, see Table 3).19 In summary, the bispyrrolidine 20 and
the piperazine 21 possess good in vitro potency and good in vivo
inhibition of liver SCD activity in the mLPD at 2 mg/kg (Table 3).20
As expected, 20 and 21 displayed a liver-selective tissue distri-
bution profile. The mouse liver/plasma (L/P) ratios (20: 60-fold; 21:
40-fold) were slightly reduced up to two folds and the liver/Harde-
rian glands (L/H) ratios (20: 40-fold; 21: 180-fold) were improved
when compared to MK-8245 (L/P: 90-fold; L/H: 20-fold) (Table 3).
This good tissue-selectivity for the liver organ is desirable, given
the connection that inhibiting SCD in the Harderian glands is asso-
ciated with eye AEs.5
dose of 2 mg/kg in the mLPD model to afford 89% liver SCD inhi-
bition at a liver exposure of 4.9 M.
Despite a good liver exposure of 2 in mice, the moderate in vivo
activity of 2 in mLPD oriented our synthetic efforts on improving
the in vivo potency by increasing the overall in vitro SCD-activity
of this class of inhibitors.
l
Since the bispyrrolidine core contained in 2 was the first
replacement explored and the fact that the thiazole is a good

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N. Lachance et al. / Bioorg. Med. Chem. Lett. 22 (2012) 980–984
Table 3
In vitro and in vivo profiles of MK-8245, 20 and 21 in mice
Mouse SCD
IC50 (nM)
In vivo
TDa
(l
M)
mLPDb
MK-8245
3
[Liver] = 2.7
89% inh. at 2 mg/kg
[Plasma] = 0.03
[Harderian glands] = 0.13
[Liver] = 4.9
49% inh. at 0.4 mg/kg
[Liver] = 1.6
lM
lM
20
21
9
[Liver] = 21.3
[Plasma] = 0.36
[Harderian glands] = 0.51
76% inh. at 2 mg/kg
[Liver] = 23.2
lM
21
[Liver] = 9.3
[Plasma] = 0.22
61% inh. at 2 mg/kg
[Liver] = 7.7
lM
[Harderian glands] = 0.05
a
TD—tissue distribution (PO, mouse (n = 2), 10 mg/kg; 6 h post dose).
mLPD (PO, mouse (n = 5), 3 h post dose); inh.—inhibition.
b
B.; Lachance, N.; Landry, F.; Li, C. S.; Mancini, J.; Normandin, D.; Pocai, A.;
Powell, D. A.; Ramtohul, Y. K.; Skorey, K.; Sørensen, D.; Sturkenboom, W.;
Styhler, A.; Waddleton, D. M.; Wang, H.; Wong, S.; Xu, L.; Zhang, L. J. Med. Chem.
2011, 54, 5082.
In conclusion, we have identified a bispyrrolidine and a pipera-
zine series as new structural motifs for SCD inhibitors. In these ser-
ies, the piperidine core present in MK-8245, and in other common
SCD-inhibitors,8 is replaced by moderately rigid heterocycles con-
necting the thiazole or isoxazole ring with the phenyl ring via a C–
N bond. SAR around the bispyrrolidine core led to the identification
of the thiazole heterocycle and the 2-chloro-5-trifluoromethoxy-
phenyl in 20, as an excellent combination for both in vitro potency
and in vivo efficacy. Presently, the exploration of the bispyrrolidine
series is suspended but any future work will need to focus on
improving mLPD activity in this series by increasing in vitro inhib-
itory activity for Rat SCD and Rat Hep assays, and to evaluate the
therapeutic profile in a 4-week chronic dosing model.
6. Mouse liver pharmacodynamic model (mLPD) is expressed in percentage (%)
inhibition and is used to assess the in vivo potency. In the mLPD experiment,
mice were fed on a high carbohydrate diet and the SCD activity was indexed 3 h
post oral dose of SCD inhibitors by following the conversion of intravenously
administered [1-14C]-stearic acid tracer to the SCD-derived [1-14C]-oleic acid in
liver lipids. The percentage (%) of inhibition of an SCD inhibitor is calculated
from the liver SCD activity index (ratio of 14C-oleic acid/14C-stearic acid) from
drug treated animals compared to a vehicle group.
7. Lachance, N.; Guiral, S.; Huang, Z.; Leclerc, J.-P.; Li, C. S.; Oballa, R. M.;
Ramtohul, Y. K.; Wang, H.; Wu, J.; Zhang, L. Bioorg. Med. Chem. Lett. 2011.
doi:10.1016/j.bmcl.2011.10.070.
8. Leading references: (a) Zhao, H.; Serby, M. D.; Smith, H. T.; Cao, N.; Suhar, T. S.;
Surowy, T. K.; Camp, H. S.; Collins, C. A.; Sham, H. L.; Liu, G. Bioorg. Med. Chem.
Lett. 2007, 17, 3388; (b) Liu, G.; Lynch, J. K.; Freeman, J.; Liu, B.; Xin, Z.; Zhao, H.;
Serby, M. D.; Kym, P. R.; Suhar, T. S.; Smith, H. T.; Cao, N.; Yang, R.; Janis, R. S.;
Krauser, J. A.; Cepa, S. P.; Beno, D. W. A.; Sham, H. L.; Collins, C. A.; Surowy, T. K.;
Camp, H. S. J. Med. Chem. 2007, 50, 3086.
Acknowledgments
9. Detailed experimental procedures: Lachance, N.; Leger, S.; Oballa, R. M.; Powell,
D.; Tranmer, G. K.; Martins, E.; Gareau, Y. WO 2010/108268 and references
cited therein.
The authors thank Dan Sørensen for NMR spectroscopic assis-
tance on gHMBC, 15N gHMBC and 1D NOESY experiments.
10. (a) During the course of this study, three separate patent applications
describing new systemically-distributed SCD inhibitors containing bicyclic
heterocycles tether were published: Zoller, G.; Voss, M. D.; Matter, H.; Herling,
A. WO 2010/028761.; (b) Chaudhari, S. S.; Thomas, A.; Gudade, G. B.; Kadam,
A.; Patil, N. P.; Khairatkar-Joshi, N.; Shah, D. M. WO 2009/037542.; (c) Zoller,
G.; Voss, M. D.; Keil, S.; Herling, A.; Matter, H. WO 2008/135141.
11. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144 and references cited
therein.
12. Girardin, M.; Alsabeh, P. G.; Lauzon, S.; Dolman, S. J.; Ouellet, S. G.; Hughes, G.
Org. Lett. 2009, 11, 1159.
13. The regiochemistry of the acetic acid side chain on the tetrazole was confirmed
by evaluation of the structures through NMR experiments: gHMBC, 15N gHMBC
and 1D NOESY.
14. Rat microsomal assay conditions: Li, C. S.; Ramtohul, Y.; Huang, Z.; Lachance, N.
WO 2006/130986.
15. Zhang, L.; Ramtohul, Y.; Gagné, S.; Styhler, A.; Guay, J.; Huang, Z. J. Biomol.
Screen. 2010, 15, 169.
16. Compounds containing a six-membered heterocycle ring pyrimidine were less
potent. Data unpublished.
17. Powell, D. A.; Ramtohul, Y.; Lebrun, M.-E.; Oballa, R.; Bhat, S.; Falgueyret, J.-P.;
Guiral, S.; Huang, Z.; Skorey, K.; Tawa, P.; Zhang, L. Bioorg. Med. Chem. Lett.
2010, 20, 6366.
18. Several substituents (F, Cl, Br, Me, CF3, SO2Me, OMe, OEt, OCH2Cyp, Ph) were
evaluated across numerous combination at the ortho, meta and para positions
on the phenyl ring. Unpublished results.
19. The available or free drug concentration in the liver homogenate was not
measured for compounds 20 and 21. Total drug concentration presented in
Table 3 supports the efficacy of MK-8245, 20 and 21 in mLPD.
20. MK-8245, 20, 21 were tested in three separate mLPD experiments; n = 5 mice
per group. A difference (10–15%) of inhibitory activity from 61% to 76% or from
76% to 89% in the mLPD is not statistically significant.
References and notes
1. Reviews: (a) Dobrzyn, P.; Dobrzyn, A. Expert Opin. Ther. Patents 2010, 20, 849
and references cited therein; (b) Liu, G. Expert Opin. Ther. Patents 2009, 19, 1169
and references cited therein.
2. Leading references: (Mice AEs): (a) Leger, S.; Black, C.; Deschenes, D.; Dolman,
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Atkinson, K. A.; Beretta, E. E.; Brown, J. A.; Castrodad, M.; Chen, Y.; Cosgrove, J.
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