Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists for the high affinity niacin receptor GPR109A

Article abstract of DOI:10.1016/j.bmcl.2010.04.013

A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity niacin receptor GPR109A. The structure-activity relationship (SAR) studies were aimed to improve activity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C

Full text of DOI:10.1016/j.bmcl.2010.04.013

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3372–3375
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists
for the high affinity niacin receptor GPR109A
a,
b
b
b
Fa-Xiang Ding a, , Hong C. Shen , Larrisa C. Wilsie , Mihajlo L. Krsmanovic , Andrew K. Taggart ,
Ning Ren b, Tian-Quan Cai b, Junying Wang c, Xinchun Tong c, Tom G. Holt c, Qing Chen c, M. Gerard Waters b,
Milton L. Hammond a, James R. Tata a, Steven L. Colletti a
*
*
a Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
b Department of Cardiovascular Diseases, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
c Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 February 2010
Revised 4 April 2010
Accepted 7 April 2010
Available online 11 April 2010
A series of pyrazolyl propionyl cyclohexenamides were discovered as full agonists for the high affinity
niacin receptor GPR109A. The structure–activity relationship (SAR) studies were aimed to improve activ-
ity on GPR109A, reduce Cytochrome P450 2C8 (CYP2C8) and Cytochrome P450 2C9 (CYP2C9) inhibition,
reduce serum shift and improve pharmacokinetic (PK) profiles.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Agonist
GPR109A
Niacin
Niacin receptor
Cyclohexenamides
Niacin (nicotinic acid), as a group B vitamin (>15–20 mg/day),
plays its physiological role as the precursor for NAD+ and NADP+.1
As an anti-dyslipidemic drug dosed 500–2000 mg/day, niacin dem-
onstrates its pharmacological utility by modifying lipid profiles.2
Particularly, niacin elevates high density lipoprotein cholesterol
(HDL-C), and reduces total plasma cholesterol, triglyceride (TG),
very low-density lipoprotein cholesterol (VLDL-C), low-density
lipoprotein cholesterol (LDL-C) and lipoprotein a (Lp(a)).3 In clini-
cal studies including the Coronary Drug Project (CDP),4 Stockholm
Ischaemic Heart Disease Study,5 HATS Trial,6 and ARBITER 2 trial,2d
niacin reduced the morbidity and mortality of patients with coro-
nary heart disease, and slowed the progression of atherosclerosis
by mono-therapy or combination therapy with simvastatin. The
most common adverse effect of niacin treatment is severe skin
vasodilation.
disclosed biaryl and tricyclic anthranilides, ureas, and cycloalkenes
as full agonists for GPR109A.10 Herein we report the discovery of
pyrazole analogs for the high affinity niacin receptor GPR109A.
To enhance activity against GPR109A, improve PK profiles and re-
duce CYP liability, we identified pyrazole, hydroxypyridine, cyclo-
hexene and an aryl substituent of cyclohexene as fragments for
optimized GPR109A agonists.
First, we studied a series of anthranilides (Fig. 1) with their
binding and [35S]GTP
cS assay data shown in Table 1. Having simi-
O
CO2H
CO2H
H
N
R
N
N
H
N
CO2H
CO2H
O
Cl
2
1a (R=H)
1b (R=OH)
R
N
N
H
The beneficial role of niacin and the discovery of GPR109A, the
high affinity niacin receptor,7 have stirred the interests of both aca-
demia8 and pharmaceutical industry9 in pursuing niacin receptor
agonists as potential therapeutic agents for cardiovascular disease
yet devoid of the skin vasodilatory effects of niacin. Previously, we
N
N
N
HO
H
N
R
O
O
4a (R=H)
4b (R=Me)
3a (R=H)
3b (R=OH)
CO2H
N
R
CO2H
R
N
N
N
H
H
N
HO
N
N
HO
N
O
O
* Corresponding authors. Tel.: +1 732 594 3232 (F.-X. Ding); tel.: +1 732 594
1755; fax: +1 732 594 9473 (H.C. Shen).
6a (R=H)
6b (R=Me)
5a (R=H)
5b (R=Me)
E-mail addresses: fa_xiang_ding@merck.com (F.-X. Ding), hong_shen@merck.
com (H.C. Shen).
Figure 1. Structures of pyrazolyl anthranilides.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.013

F.-X. Ding et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3372–3375
3373
Table 1
IC50 = 15 nM for 6a) and functional activity (EC50 = 0.28
vs EC50 = 0.75
1,3-disubstituted pyrazole 10a with respect to 1,4-disubstituted
pyrazole 9a in the competitive binding assay (IC50 = 5 nM for 10a
vs IC50 = 26 nM for 9a), 9a and 10a had similar functional activity.
l
M for 8a
In vitro SAR against GPR109A for anthranilides 1–6
l
M for 6a) (Table 2). Despite the higher affinity of
Compds
R
3H-niacin binding
Serum shiftb
hGTP
EC50
c
(
S
l
a
a
IC50
(lM)
M)
Niacin
1a
1b
2
3a
3b
4a
4b
5a
5b
6a
0.14
1
1.0
H
OH
0.019
0.004
0.31
0.12
0.045
9.5
The a-methyl group of the amide led to slightly reduced activities,
>5000
as shown by the activity of 8a versus 8b, 9a versus 9b, and 10a ver-
sus 10b. Further saturation of the cyclohexene ring such as cis
racemic 1,2-substituted cyclohexane isomers 11 resulted in a dras-
tic loss of activity.
To improve the activity, we modified the 4-position of the
cyclohexene moiety of 10a with various alkyl and aryl
substituents. With excellent binding activity (IC50s <20 nM), the
aryl-substituted analogs exhibited excellent functional activity.12
In particular, 12d and 12e demonstrated remarkable binding affin-
ity (6 nM and 5 nM, respectively) and functional activity (67 nM
and 62 nM, respectively).
H
OH
H
Me
H
Me
H
0.26
40
70
3.9
0.032
0.024
0.077
0.058
0.025
0.015
0.091
0.34
0.093
1.1
60
170
200
1.3
0.94
0.75
3.0
6b
Me
a
Value are means of at least three experiments, average standard deviation is
about 20%.
b
3H-Niacin binding with 4% human serum.
We then measured the compound-induced inhibition of lipoly-
sis in human adipocytes (Table 3). Compounds 4a, 4b and 7 sup-
pressed the lipolysis similar to niacin, indicating the efficacy of
these compounds in whole cells.
lar maximum level of response as niacin in the GTPcS assay, all
analogs described in this Letter are characterized as full agonists.
Compound 1b containing a terminal hydroxyl group was 3–5-fold
more active against GPR109A than 1a. Despite its good activity,
compound 1b had a poor PK profile with only 5% bioavailability
(Table 5) and more than 5000-fold serum shift in the competitive
binding assay with 4% human serum. Furthermore, 1b was a potent
inhibitor for CYP2C8 and 2C9 (Table 4), and potentially had bioac-
tivated covalent binding due to the phenolic moiety. To overcome
these issues, our first approach was to replace the inner phenyl
group with a pyrazole, as shown by analogs 2–6 in Figure 1.
Although less active than the biphenyl analogs 1a and 1b, analogs
bearing the inner pyrazole group had significantly reduced serum
shift in the binding assay (compounds 3–6, Table 1). Similar to ana-
log 1b, by incorporating a terminal hydroxyl group in the pyrazole
class, 3b was approximately 10-fold more active than 3a. Concern-
ing the potential covalent binding of the electron-rich phenol
group, we replaced 4-hydroxyphenyl with 4-hydroxy-2-pyridyl,
as shown in compound 5 and 6, to reduce the electron density of
the aromatic ring. This structural change gave no significant
change of activity in the binding assay, despite some loss of activity
The biphenyl series generally posed issues on CYP2C8 and 2C9
inhibition. One such example was 1b, a potent inhibitor of both
CYP2C8 and 2C9 enzymes with submicromolar IC50s (Table 4).
The presence of pyrazole as the inner ring, the substitution pattern
of pyrazole, and cyclohexene replacement of anthranilide (Fig. 2)
all played a profound role in reducing CYP inhibition. With respect
to 1b, the 1,3-disubstituted pyrazole analog 2 reduced inhibition of
both CYP2C8 and 2C9 with IC50s in a low micromolar range. Fur-
thermore, compounds 3a, 4a, and 4b containing a 1,4-disubstituted
pyrazole, had further reduced inhibition against both CYP enzymes
(IC50 = 15–34 lM). Finally, the cyclohexene analogs 7 and 9a com-
pletely removed CYP2C8 and 2C9 inhibition. The incorporation of
Table 2
In vitro SAR against GPR109A for cylohexenamides 7–10
Compds
R
3H-niacin
Serum
shiftb
hGTPcS
binding
a
a
IC50
(l
M)
EC50
in the GTP
tution at the five position of the pyrazole in 4a slightly increased
the binding affinity with respect to 3b. The introduction of
methyl group to 4a and 6a resulted in less active compounds, 4b
and 6b. Conversely, the -methyl group was beneficial to activity
cS assay (6a vs 4a, 6b vs 4b, Table 1). The methyl substi-
(lM)
7
8a
8b
9a
0.026
0.007
0.046
0.026
0.022
0.005
0.010
1.31
0.014
0.009
0.012
0.006
50
0.35
0.28
0.77
0.20
0.54
0.23
0.37
17.9
0.17
0.13
0.23
0.067
0.062
0.095
a
-
H
CH3
H
CH3
H
CH3
240
a
9b
in the case of 5b, a more active compound than 5a.
10a
10b
11
12a
12b
12c
12d
1000
900
After adopting the 4-hydroxypyridyl-pyrazole as the optimized
biaryl group, we replaced the anthranilide moiety with the cyclo-
hexenamide shown in Figure 2.11 In comparison with 6a, the
replacement of a 2-carboxyphenyl with a 2-carboxy 1-hexenyl
group in 8a improved the binding affinity (IC50 = 7 nM for 8a vs
R1 = CH3 (R); R2 = H
290
110
40
R
R
R
R
1 = CH2CH2CH3; R2 = H
1 = 3-F-phenyl; R2 = H
1 = 2-F-3-F-phenyl;
2 = H
30
12e
12f
R1 = H; R2 = 3-F-5-F-
phenyl
0.005
0.015
100
30
O
O
O
R1 = 3-F-4-F-5-F-phenyl;
R
2 = H
N
H
N
H
HO
N
HO
HO
N
N
CO2H
R
R
CO2H
CO2H
N
N
N
a
Value are means of at least three experiments, average standard deviation is
about 20%.
7
8
3H-Niacin binding with 4% human serum.
b
H
N
N
H
HO
HO
N
N
N
R
CO2H
CO2H
N
N
N
O
10
9
Table 3
CO2H
H
H
N
HO
N
In vitro inhibition of lipolysis in human adipocytesa
N
N
N
N
N
O
Compd
IC50 M)
Niacin
0.08
4a
4b
7
O
11
12
R2
R1
(l
0.04
0.06
0.07
a
Free glycerol was measured to calculate IC50s for the lipolysis inhibition assay.
Figure 2. Structures of pyrazolyl propionyl cyclohexenamides.

3374
F.-X. Ding et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3372–3375
Table 4
CO2Et
N
CO2Et
b
CO2Et
N
N
CYP2C8 and 2C9 inhibition for compoundsa
H2N
N
a
HN
O2N
N
N
N
12ea
12eb
CO2Et
Compd
1b
2
3a
4a
4b
7
9a
12e
12ec
CYP2C8 IC50
CYP2C9 IC50
(
(
l
l
M)
M)
<0.4
<0.4
2.7
2.5
—
15
19
15
34
22
>100
>100
—
>50
7.7
23
CO2Et
N
N
c,d
e
f
AcO
N
HO
N
N
N
N
a
The CYP2C8 inhibition assay in human liver microsomes used taxol and
12ed
12ee
montelukast as the substrate and positive control, respectively. The CYP2C9 inhi-
bition assay in human liver microsomes used diclofenac and sulfaphenazole as the
substrate and positive control, respectively.
CO2Et
N
CH2OH
N
g
h
PMBO
N
PMBO
N
N
12eg
12ef
CO2Me
CO2Me
CH2Br
N
N
j,k
i
Table 5
PMBO
N
PMBO
PMBO
N
Mouse or rat PKa
N
N
12ei
12eh
Compd F%
Cl (mL/min/ Vdss (L/
Cmax
M)
T1/2
(h)
AUCpo
(lM h kg/mg)
N
CO2H
N
CONH2
p,q
l,m
kg)
4.6 18
21 17
2.5 26
52
46
kg)
(
l
N
PMBO
o
N
N
1bb
3bb
4ab
7b
0.35
3.56
0.88
0.68
0.40
0.36
0.53
0.93
0.48
0.03
4.78
11.53
0.03
2.0
3.5
1.1
4.8
3.3
0.74
5.5
0.11
0.58
0.1
N
12ek
12ej
O
O
O
O
O
n
3.5
1.2
6.5
O
F
9ab
12dc
12ec
19
0.06
1.6
O
OTf
4.5 28
39 8.6
12el
12em
12en
TfO
1.58
F
O
O
a
Formulations: 0.2 mg/mL ethanol/PEG/water (10:40:50). IV dose: 1 mg/kg
(n = 3). PO dose: 2 mg/kg (n = 3). Blood concentration was determined by LC/MS/MS
O
F
s
O
F
r
F
following protein precipitation with acetonitrile.
O
O
b
Mouse PK.
Rat PK.
c
12eo
12ep
12eq
F
F
F
CO2Me
H
N
t
PMBO
N
N
N
O
F
12er
an aryl group in 12e increased the CYP inhibition, but was still sig-
nificantly better than the lead compound 1b.
CO2H
u,v
H
N
F
F
HO
N
Besides reducing CYP2C8 and 2C9 liability (Table 4), in general,
the replacement of the inner phenyl group with a pyrazole, and the
anthranilide moiety with a cyclohexenamide provided significantly
improved mouse or rat PK parameters (7 and 9a vs 1b, 3b, and 4a
in Table 5). In addition, the fluoroaryl substitution position of the
cyclohexenyl group appeared to have a substantial impact on rat
PKs of analogs, as exemplified by 12d and 12e. With respect to
12d, compound 12e had an eightfold higher bioavailability and half
life, a threefold lower clearance, and a 26-fold higher oral expo-
sure. Comparing 3b and 4a, it appeared that the extra methyl
group present in 4a led to the significant reduction of Cmax, half life,
normalized AUC and bioavailability.
The synthesis of analog 12e, as a representative example, was
achieved over 22 steps in total as shown in Scheme 1. The prepa-
ration of the key intermediate 12ek was commenced with com-
mercially available pyrazole 12ea. The nucleophilic aromatic
substitution of 2-bromo-5-nitropyridine with 12ea provided
12eb. The reduction of the nitro group in 12eb was followed by a
three-step sequence to convert the resulting amino group to a hy-
droxyl group via an intermediate diazonium tetrafluoroborate salt.
The hydroxyl group of 12ee was subsequently protected as a PMB
ether. The two-carbon chain extension led to carboxylic acid 12ej,
which was then converted to amide 12ek through an active succ-
inimidyl ester intermediate in excellent yield. Intermediate 12eq
was synthesized in six steps starting from 12el. The Pd-catalyzed
amidation of 12eq with 12ek formed 12er. Finally, the deprotec-
tion of the PMB group followed by hydrolysis afforded the desired
product 12e. The overall synthesis has a convergent nature.
In conclusion, we have identified a new class of pyrazolyl propi-
onyl cyclohexenamides as highly active full agonists for the niacin
receptor GPR109A. The sequential employment of pyrazole,
hydroxypyridine, cyclohexene, and an aryl substitution of cyclo-
hexene eventually led to the discovery of 12e with excellent activ-
ity against GPR109A, very weak CYP2C8 and 2C9 inhibition, and a
good rat PK profile.
N
N
O
12e
F
Scheme 1. Reagents and conditions: (a) 2-bromo-5-nitropyridine, NaH, DMF, 0 °C
to rt, 0.5 h, 88%; (b) Zn, AcOH, 60 °C, 0.5 h, 99%; (c) NaNO2, 40% HBF4, 0 °C, 2 h; (d)
Ac2O, 65 °C, 16 h, 52% in two steps; (e) cat. H2SO4, EtOH, reflux, 16 h, 97%; (f) NaH,
PMB-Cl, cat. NaI, DMF, 90 °C, 1 h, 95%; (g) LiBH4, THF, reflux, 24 h, 100%; (h) Ph3P,
NBS, pyridine, CH2Cl2, 0 °C, 1.5 h, 77%; (i) dimethyl malonate, NaH, DMF, 0 °C to rt,
1 h, 98%; (j) LiOH, THF/MeOH/H2O (3:1:1), rt, 1 h, 92%; (k) DMF, 130 °C, 20 min,
94%; (l) N-hydroxy succinimide, EDCI, CH2Cl2, 3 h, 99%; (m) 28% NH3/H2O; dioxane,
2 h, 97%; (n) LiHMDS, 2-(N,N-bistrifluoro-methylsulfonylamino)-5-chloropyridine,
THF, À78 °C to rt, 2 h, 72%; (o) 3,5-difluorophenylboronic acid, Pd(PPh3)2Cl2,
Na2CO3, THF, rt, 2 h, 86%; (p) H2, 10% Pd/C, MeOH, rt, 16 h; (q) 3 N HCl, THF, rt, 5 h,
80% in two steps; (r) LiHMDS, methyl cyanoformate, THF, À78 °C to rt, 3 h, 62%; (s)
NaH, 2-(N,N-bis-trifluoromethylsulfonylamino)-5-chloropyridine, THF, 0 °C to rt,
2 h, 68%; (t) Pd2(dba)3, 12ek, xantphos, Cs2CO3, dioxane, 80 °C, 16 h; 49%; (u) TFA,
triisopropylsilane, CH2Cl2; 0 °C to rt, 20 min; (v) LiOH, THF/MeOH/H2O(3:1:1), 0 °C
to rt, 15 h, 40% in two steps.
References and notes
1. (a) Elvehjem, C. A.; Madden, R. J.; Strong, F. M.; Wooley, D. W. J. Biol. Chem.
1938, 123, 137; (b) Holman, W. I.; De Lange, D. J. Nature 1950, 165, 112.
2. (a) Mack, W. J.; Selzer, R. H.; Hodis, H. N.; Erickson, J. K.; Liu, C. R.; Liu, C. H.;
Crawford, D. W.; Blankenhorn, D. H. Stroke 1993, 24, 1779; (b) Nikkila, E. A.;
Viikinkoski, P.; Valle, M.; Frick, M. H. Br. Med. J. 1984, 289, 220; (c) Pritzker, L. B.
Crit. Rev. Clin. Lab. Sci. 1998, 35, 603; (d) Taylor, A. J.; Sullenberger, L. E.; Lee, H.
J.; Lee, J. K.; Grace, K. A. Circulation 2004, 110, 3512; (e) Carlson, L. A. J. Int. Med.
2005, 258, 94.
3. Knopp, R. H. N. Eng. J. Med. 1999, 341, 498.
4. (a) The Coronary Drug Project Research Group J. Am. Med. Assoc. 1975, 231, 360;
(b) Canner, P. L.; Berge, K. G.; Wenger, N. K.; Stamler, J.; Friedman, L.; Prineas, R.
J.; Friedewald, W. J. Am. Coll. Cardiol. 1986, 8, 1245.
5. Carlson, L. A.; Rosenhamer, G. Acta Med. Scand. 1988, 223, 405.
6. Brown, B. G.; Zhao, X.-Q.; Chait, A.; Fisher, L. D.; Cheung, M.; Morse, J. S.;
Dowdy, A. A.; Marino, E. K.; Bolson, E. L.; Alaupovic, P.; Frohlich, J.; Albers, J. J. N.
Eng. J. Med. 2001, 345, 1583.
7. (a) Schaub, A.; Futterer, A.; Pfeffer, K. Eur. J. Immunol. 2001, 31, 3714; (b) Wise,
A.; Foord, S. M.; Fraser, N. J.; Barnes, A. A.; Elshourbagy, N.; Eilert, M.; Ignar, D.

F.-X. Ding et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3372–3375
3375
M.; Murdock, P. R.; Steplewski, K.; Green, A.; Brown, A. J.; Dowell, S. J.; Szekeres,
P. G.; Hassall, D. G.; Marshall, F. H.; Wilson, S.; Pike, N. B. J. Biol. Chem. 2003, 278,
9869; (c) Tunaru, S.; Kero, J.; Schaub, A.; Wufka, C.; Blaukat, A.; Pfeffer, K.;
Offermanns, S. Nat. Med. 2003, 9, 352.
T. G.; Waters, M. G.; Hammond, M. L.; Tata, J. R.; Colletti, S. L. J. Med. Chem.
2007, 50, 6303; (c) Raghavan, S.; Tria, G. S.; Shen, H. C.; Ding, F.-X.; Taggart, A.
K. P.; Ren, N.; Wilsie, L. C.; Krsmanovic, M. L.; Holt, T. G.; Wolff, M. S.; Waters,
M. G.; Hammond, M. L.; Tata, J. R.; Colletti, S. L. Bioorg. Med. Chem. Lett. 2008,
18, 3163; (d) Shen, H. C.; Ding, F.-X.; Frie, J.; Chen, W.; Deng, Q.; Taggart, A.;
Ren, N.; Carballo-Jane, E.; Cheng, K.; Cai, T.; Wolff, M.; Waters, G.; Hammond,
M.; Tata, R. J.; Colletti, S. L. J. Med. Chem. 2009, 52, 2587.
8. Herk, T.; Brussee, J.; Nieuwendijk, A. M. C. H.; Klein, P. A. M.; Ijzerman, A. P.;
Stannek, C.; Brumeister, A.; Lorenzen, A. J. Med. Chem. 2003, 46, 3945.
9. For reviews: (a) Semple, G.; Boatman, P. D.; Richman, J. G. Curr. Opin. Drug Disc.
Dev. 2007, 10, 452; (b) Boatman, P. D.; Richman, J. G.; Semple, G. J. Med. Chem.
2008, 51, 7653; (c) Shen, H. C.; Colletti, S. L. Expert Opin. Ther. Patents 2009, 19,
957. and patent references cited therein.
10. (a) Shen, H. C.; Szymonifka, M. J.; Kharbanda, D.; Deng, Q.; Carballo-Jane, E.;
Wu, K. K.; Wu, T.-J.; Cheng, K.; Ren, N.; Cai, T.-Q.; Taggart, A. K.; Wang, J.; Tong,
X.; Waters, M. G.; Hammond, M. L.; Tata, J. R.; Colletti, S. L. Bioorg. Med. Chem.
Lett. 2007, 17, 6723; (b) Shen, H. C.; Ding, F.-X.; Luell, S.; Forrest, M. J.; Carballo-
Jane, E.; Wu, K. K.; Wu, T.-J.; Cheng, K.; Wilsie, L. C.; Krsmanovic, M. L.; Taggart,
A. K.; Ren, N.; Cai, T.-Q.; Deng, Q.; Chen, Q.; Wang, J.; Wolff, M. S.; Tong, X.; Holt,
11. Shen, H. C.; Ding, F.-X.; Raghavan, S.; Deng, Q.; Luell, S.; Forrest, M. J.; Carballo-
Jane, E.; Wilsie, L. C.; Krsmanovic, M. L.; Taggart, A.; Wu, K. K.; Wu, T.-J.; Cheng,
K.; Ren, N.; Cai, T.-Q.; Chen, Q.; Wang, J.; Wolff, M. S.; Tong, X.; Holt, T. G.;
Waters, M. G.; Hammond, L. M.; Tata, J. R.; Colletti, S. L. J. Med. Chem. 2010, 53,
2666.
12. Schmidt, D. R.; Smenton, A. L.; Raghavan, S.; Shen, H. C.; Ding, F.; Carballo-Jane,
E.; Luell, S.; Ciecko, T.; Holt, T.G.; Wolff, M. S.; Taggart, A. K. P.; Wilsie, L. C.;
Krsmanovic, M. L.; Ren, N.; Blom, D.; Cheng, K.; McCann, P. E.; Waters, M.G.;
Tata, J. R.; Colletti, S. L. Bioorg. Med. Chem. Lett. 2010, 20, 3426.