A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity

Article abstract of DOI:10.1016/j.bmcl.2011.10.113

A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in

Full text of DOI:10.1016/j.bmcl.2011.10.113

Bioorganic & Medicinal Chemistry Letters 22 (2012) 415–420
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A novel series of glucagon receptor antagonists with reduced molecular
weight and lipophilicity
⇑
,
Kevin J. Filipski , Jianwei Bian, David C. Ebner, Esther C.Y. Lee, Jian-Cheng Li, Matthew F. Sammons,
Stephen W. Wright, Benjamin D. Stevens, Mary T. Didiuk, Meihua Tu, Christian Perreault, Janice Brown,
Karen Atkinson, Beijing Tan, Christopher T. Salatto, John Litchfield, Jeffrey A. Pfefferkorn, Angel Guzman-
Perez
Pfizer Worldwide Research & Development, Eastern Point Rd, Groton, CT 06442, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and amino-
pyrazoles have lower molecular weight and increased polarity such that the molecules fall into better
drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have
good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound
49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge
experiment.
Received 16 August 2011
Revised 25 October 2011
Accepted 31 October 2011
Available online 6 November 2011
Keywords:
Glucagon receptor antagonist
Diabetes
Ó 2011 Elsevier Ltd. All rights reserved.
Pyrazole ether
Aminopyrazole
Type 2 Diabetes Mellitus (T2DM) is a growing worldwide epi-
demic currently affecting an estimated 285 million people.1
Although several classes of diabetic therapies are routinely used
clinically, there remains a significant unmet medical need for addi-
tional therapies.2 T2DM is partially characterized by elevated and
dysregulated hepatic glucose output. Glucagon is a 29-amino acid
peptide that acts as the principle counter-regulatory hormone to
insulin in the control of glucose homeostasis.3 Through binding
of glucagon to the G-protein coupled glucagon receptor, hepatic
glycogenolysis and gluconeogenesis are stimulated resulting in en-
hanced hepatic glucose production. It is therefore postulated that
blocking the action of the glucagon receptor would lead to
improved glycemic control in T2DM patients.4
subsequent work by many groups including work leading to the
discovery of Merck clinical candidate MK-0893 (3)8 and com-
pound 4.9
Most of the b-alanine-containing GCGRA antagonists are rela-
tively high molecular weight, lipophilic molecules (Figure 1) situ-
ated at the edge of optimal drug-like space as defined by Lipinski
and others. This could theoretically result in sub-optimal biophar-
maceutical properties.10 As part of a discovery program, we sought
to develop a series of small molecule glucagon receptor antagonists
with reduced molecular weight and lipophilicity with the goal of
improving pharmacokinetic (PK) and safety properties.11 Specifi-
cally, we sought potent and selective antagonists with molecular
weight <500 and logD <3.
Over the last two decades, various research teams have
brought forward both large and small molecules that act as glu-
cagon receptor (GCGR) antagonists.4,5 One notable early molecule
is Bay 27-9955 (1) that clinically demonstrated a reduction in
glucagon-induced glucose excursion by modulating hepatic glu-
cose production in humans.6 Researchers at Novo-Nordisk later
disclosed a series containing a b-alanine side chain in structures
such as NNC 25-0926 (2).7 This motif has been incorporated into
We identified a pyrazole ether series of glucagon receptor
antagonists through our discovery program. The syntheses of these
analogs were accomplished according to Scheme 1. Dimethyl
malonate (5) was condensed with ethyl diazoacetate to form di-
methyl ester 6.12 Hot concentrated hydrochloric acid led to hydro-
lysis and decarboxylation of 6 affording hydroxypyrazole 7. The
pyrazole nitrogen was selectively trityl protected by initial in situ
protection of the hydroxy with a trimethylsilyl group. The tran-
sient TMS group was then hydrolyzed under mild aqueous basic
conditions to provide 8. Separately, ethyl 4-iodobenzoate 9 was
converted to alcohol 10 by formation of the Grignard species fol-
lowed by addition into butyraldehyde.13 Compound 10 was then
converted to the methanesulfonate 11 under standard conditions.
⇑
Corresponding author. Tel.: +1 617 551 3267; fax: +1 617 551 3082.
E-mail address: kevin.filipski@pfizer.com (K.J. Filipski).
Present address: Pfizer Worldwide Research
Memorial Dr., Cambridge, MA 02139, USA.
& Development, RTC 367, 620
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.113

416
K. J. Filipski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 415–420
O
O
F
N
H
OH
OH
OH
O
N
Cl
NH
(+)
Cl
1
2
Bay 27-9955
MW = 342
clog D = 7.27
NNC 25-0926
MW = 582
clog D = 3.34
O
O
O
O
N
H
OH
N
H
OH
OMe
N
N
NH
F
Cl
Cl
Cl
3
4
MW = 521
clog D = 3.92
MK-0893
MW = 588
clog D = 3.87
Figure 1. Structure, molecular weight, and clog D (calculated distribution coefficient) for key glucagon receptor antagonists.
Ether 12 was formed by displacement of mesylate 11 with the an-
ion of hydroxypyrazole 8. The trityl group was removed with in situ
generated HCl to give 13, which was hydrolyzed under basic con-
ditions to form benzoic acid 14. Standard peptide coupling condi-
tions were used to produce the key amide intermediate 15,
which was subsequently coupled with 3-iodotoluene and a variety
of other aryl halides, using Buchwald’s copper-catalyzed amination
conditions to give esters such as 16.14 Compound 16 and similar
intermediates were finally hydrolyzed under basic conditions to
provide 17 as a racemic mixture.
Aminopyrazoles were synthesized according to the procedure
shown in Scheme 2. Nitropyrazole 18 was coupled with 4-trif-
luoromethylphenylboronic acid under Chan-Lam conditions to form
19.15 The nitro group was reduced by catalytic hydrogenation to give
amine 20. Separately, 4-iodobenzoic acid 21 was first esterified to
tert-butyl ester 22 using Wright’s conditions,16 and then converted
to ketone 23 by formation of the cuprate and addition into butyryl
chloride.17 A decaborane-mediated reductive amination provided
24,18 which was hydrolyzed to acid 25. A standard amide formation
gave racemic 26, which was separated into enantiomers 27 and 28
by SFC. The enantiomers were separately hydrolyzed to provide ana-
logs 29 and 30.
binding assay was performed in the presence of low BSA concen-
trations (0.2%) while functional activity was determined in the
presence of 4% BSA in order to provide an estimate of plasma
bound total potency. As can be observed in the series 31–33, a
methyl group in the ortho position is not tolerated while in the
meta or para position, modest binding potency is observed without
measurable functional activity. Therefore, subsequent work was
focused to the meta and para positions for substitution. Ethyl ana-
logs 34 and 35 show improved potency both in binding and func-
tional assays. 3-Chloro 36 and 4-chloro 37 are similar in potency to
their methyl counterparts. Introducing polarity to the substituent,
as with methoxy-substituted 38 and 39 decreases activity as com-
pared to the ethyl-substituted analogs. 4-Trifluoromethyl-substi-
tuted 40 shows good potency in both assays. Finally, efforts to
replace the phenyl ring of 40 with pyridine derivatives 41 and
42, resulted in greatly reduced activity.
Based on the positive results with the 4-trifluoromethyl-
substituted analog 40, this structure was chosen for further explo-
ration (Table 2). This analog was first resolved into its enantiomers
by SFC to give 43 and 44. The (–)-isomer (44) was determined to be
the more potent enantiomer with a binding Ki of 91 nM and func-
tional activity Kb of 520 nM. The molecular weight is a desirable
475 and the logD is 2.31, both values in our target zone. The pas-
sive permeability20 is also good, solubility modest, and HLM stabil-
ity excellent.
SAR of the pyrazole ether series is shown in Table 1. In each of
these cases analogs were tested as racemates. The in vitro potency
of test compounds was assessed using both binding and functional
assay formats. The binding affinity of compounds for the human
glucagon receptor was determined by their ability to displace
Replacing the ether linkage with an amine was also examined.
To our delight this modification improved both binding potency
and functional activity with the more active (+) enantiomer 45.
Even though the lipophilicity was decreased (logD = 1.73), perme-
ability was conserved. Importantly, solubility was greatly in-
creased and microsomal stability remained excellent. Changes to
[
125I] Glucagon-Cex from membranes containing the human gluca-
gon receptor,19 while functional activity was determined by the
ability of these compounds to inhibit glucagon-induced cAMP pro-
duction in a cell line expressing the human glucagon receptor. The

K. J. Filipski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 415–420
417
CO2Me
HO
O
O
HO
a
b
N
N
NH
N
MeO
OMe
R1
MeO2C
7
: R1 = H
5
6
c
8: R1 = Tr
CO2Et
CO2Et
d
f
I
O
R2
9
10
: R2 = H
11: R2 = Ms
e
CO2Et
O
R4
h
O
N
O
N
N
NH
R3
14
12
: R3 = Tr
13: R3 = H
: R4 = OH
i
g
15: R4 = HNCH2CH2CO2tBu
j
O
O
O
O
N
OH
N
H
OtBu
H
k
O
O
N
N
N
N
16
17
(+/-) -
Scheme 1. Synthetic method for synthesis of pyrazole ethers. Reagents and conditions: (a) i. Na, MeOH, 0 °C, ii. ethyl diazoacetate, 23 °C, 3 d, iii. 5 N HCl, 23 °C; (b) conc. HCl,
reflux, 16 h, 47% over two steps; (c) i. TMS-Cl, Et3N, CH3CN, 0 – 23 °C, 2 h, ii. TrCl, 23 °C – reflux, 17 h, iii. aq. sat. NaHCO3, 23 °C, 1 h, 66%; (d) i. iPrMgCl-LiCl, THF, -40 °C, 1 h, ii.
butyraldehyde, -40 – 23 °C, 1 h, 93%; (e) MsCl, Et3N, DCM, 0 °C, 90 min, 100%; (f) NaH, DMF, 23 °C, 23 h, 61%; (g) AcCl, EtOH, 0 – 70 °C, 2 h; 92%; (h) 10% aq. NaOH, THF, 70 °C,
16 h, 100%; (i) b-alanine t-butyl ester hydrochloride, HATU, Et3N, DCM, 30 °C, 16 h; 80%; (j) 3-iodotoluene, CuI, trans-N,N’-dimethylcyclohexane-1,2-diamine, K2CO3, toluene,
110 °C, 24 h; (k) TFA, DCM, 30 °C, 2.5 h.
the alkyl region were then explored with 3,3,3-trifluoropropyl and
cyclopentyl replacing the propyl side chain. These analogs were
still in the desired lipophilicity space and potency was improved.
Permeability and solubility were retained, however HLM stability
of 49 was poor. Interestingly, the less potent cyclopentyl enantio-
mer 50 had lower HLM clearance than the more potent enantiomer
and still had acceptable potency. Across this class, solubility was
potency was determined by its ability to displace [125I] GIP from
membranes expressing the hGIP receptor. Here, the margin of
selectivity was smaller with compounds ranging from 10- to 80-
fold selective.
Based on their favorable in vitro profiles, several analogs were
chosen for in vivo pharmacokinetic characterization. Pyrazole ether
44, propylamine 45, 3,3,3-trifluoropropylamine 47, and both cyclo-
pentylamine enantiomers 49 and 50 were investigated in i.v. and
oral rat PK studies. Results are shown in Table 4. In general these
compounds showed moderate to high clearance. Based on their
stability in rat liver microsomes, the major clearance mechanism
is assumed to be non-oxidative, likely biliary. Due in part to their
high in vivo clearances, these compounds also showed generally
short half lives and low oral bioavailability.
high (310
– 550 lM) [compare to reference compound 4
(22 M)]. Overall, many of the best compounds from this work
l
compared well against comparator compounds 1 – 3 with respect
to binding and functional potency (compare Table 1 entries 1–4
with Table 2). Compound 4 does offer greater potency, however.
To verify selectivity against other class B GPCR’s, selected com-
pounds were screened in both human GLP-1 and human GIP bind-
ing assays (Table 3). A compound’s GLP-1 potency was determined
by its ability to displace [125I] GLP-1 from membranes expressing
the hGLP-1 receptor. Tested analogs were determined to be highly
selective for the glucagon receptor over the GLP-1 receptor with ra-
tios falling between 50- and 500-fold selective. A compound’s GIP
Two compounds with more favorable rat PK profiles, 44 and 50,
were then taken into dog i.v. PK studies, with results shown in
Table 5. Gratifyingly, clearance values in dog were much lower indi-
cating a significant species difference in clearance. Half lives in dog
were short to moderate and exposure was good. Investigations into

418
K. J. Filipski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 415–420
H2N
O2N
N
N
N
N
O2N
a
b
N
NH
CF3
CF3
18
19
20
CO2tBu
CO2R1
d
e
I
O
21
: R1 = OH
23
c
22: R1 = tBu
CO2H
CO2tBu
HN
f
HN
N
N
N
N
25
CF3
CF3
O
24
g
O
O
O
N
H
OEt
N
H
OH
HN
i
HN
N
N
N
N
CF3
CF3
26
29
(+) -
h
(−) - 30
(+) - 27
28
(−) -
Scheme 2. Synthetic method for synthesis of aminopyrazoles. Reagents and conditions: (a) 4-trifluoromethylphenylboronic acid, Cu(OAc)2, pyridine, DCM, 4 Å MS, 23 °C, 3 d,
95%; (b) H2, 40 psi, 10% Pd/C, EtOH, 99%; (c) MgSO4, H2SO4, tBuOH, DCM, 23 °C, 2 d, 15%; (d) i. iPrMgCl-LiCl, THF, -40 °C, 1 h, ii. CuI, -15 °C, 15 min, iii. butyryl chloride, -40 –
23 °C, 16 h, 83%; (e) decaborane, MeOH, 23 °C, 16 h, 30%; (f) TFA, DCM, 23 °C, 30 min, 100%; (g) b-alanine ethyl ester hydrochloride, HOAt, EDAC, Et3N, DCM, 23 °C, 2.5 h, 83%;
(h) chiral SFC: 75/25 CO2/EtOH, Chiralcel OJ-H; (i) 1 N aq. NaOH, MeOH, 23 °C, 0.5 – 2 h, 89–100%.
the species most likely to be predictive of human pharmacokinetic
behavior for this and related series are in progress.
model in rats.7b In Wistar-Han rats at time = 0, one of three
doses of compound 49 or vehicle alone were dosed intrave-
To assess their potential safety liabilities, selected compounds
from this series were screened in a transformed human liver epi-
thelial (THLE) cell cytotoxicity assay.21 This assay measures ATP
depletion as a determinant of general cellular toxicity. Activity is
reported as the dose predicted to kill 50% of cells following a
72 h exposure, with compounds 44, 49, and 50 having IC50’s of
nously. At 15 min, a 3 lg/kg i.v. bolus of glucagon was adminis-
tered to elicit a glucose excursion. Blood glucose levels were
monitored at the following time points: 0, 10, 26, 32, 50, and
80 min. Results, shown in Figure 2, show a dose-dependent
reduction in glucose excursion by compound 49. At the 11 min
time point, glucose levels, compared to vehicle, were reduced
12, 20, and 24% at doses of 1, 10, and 30 mg/kg, respectively.
Higher doses showed an extended effect. Plasma levels of 49
90, 235, and 166
lM, respectively. This compares favorably to ref-
erence compounds 3 (IC50 = 38
l
M) and 4 (IC50 = 55 M), lending
l
some evidence to the improved safety profile achieved by reducing
at 11 min were 300
37, 2285
140, and 20950
1374 ng/
the lipophilicity.
mL, respectively. In an in vitro rat GCGRA functional assay using
similar conditions to the human assay, the Kb of 49 was
2.34 lM.
To examine whether this series of analogs displayed efficacy
in vivo, compound 49 was tested in an i.v. glucagon challenge

K. J. Filipski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 415–420
419
Table 1
Binding potency and functional activity of glucagon receptor antagonists 1–4, 31–42
O
O
N
H
OH
O
(+/-)
N
N
A 2
B
3
R
4
R
A
B
hGCGR binding Ki (
l
M)a
hGCGR cAMP Kb (l
M)a
1
2
3
4
—
—
—
—
—
—
—
—
C
C
C
C
C
C
C
C
C
C
N
C
—
—
—
—
C
C
C
C
C
C
C
0.356
0.085
0.070
0.004
14.7b
1.11
0.968
0.556
0.214
1.09
0.600
2.16
1.98
0.126
1.19
1.45
0.078
0.430
0.266
0.018
>23.6
>20.9
>12.9
4.53
3.42
16.9
>7.52
>19.1
>21.3
0.992
16.4
31
32
33
34
35
36
37
38
39
40
41
42
2-Me
3-Me
4-Me
3-Et
4-Et
3-Cl
4-Cl
3-OMe
4-OMe
4-CF3
4-CF3
4-CF3
C
C
C
C
N
21.5
a
Reported as the geometric mean of n P 2 determinations except where otherwise noted.
Reported as n = 1.
b
Table 2
Compound properties of glucagon receptor antagonists 43–50
O
O
N
H
OH
R
A
N
N
CF3
R
Optical
Rotation
Sign
A
MW
(g/
mol)
logDa hGCGR
hGCGR
cAMP Kb
(nM)b
MDCKII-LE
Kinetic
HLM Clint,
(mL/min/kg)
RLM Clint,
app
(mL/min/kg)
app
Binding Ki
Permeability (Â10À6
cm/s)c
Solubility
(nM)b
(l
M)d
43
44
45
46
+
–
+
–
O
O
475
475
2.33
2.31
1.73
1.77
430
91
1230
520
7.74
5.87
8.81
2.76
53
34
<25
<25
<25
<25
77
<8.0
<8.0
<8.0
NH 474
NH 474
19
310
550
500
67
3300
F3C
F3C
47
48
+
–
NH 528
NH 528
1.67
1.76
12
48
100
520
3.48
3.80
490
490
<8.0
<8.0
<25
<25
49
50
+
–
NH 501
NH 501
2.27
2.29
9
120
320
6.34
7.54
320
310
91
<25
30
17
<8.0
a
b
c
pH 7.4 octanol/buffer shake-flask method.
Reported as the geometric mean of n P 2 determinations.
This is a low transporter-containing MDCK cell line. See Ref. 20 for details.
Solubility at pH 6.5.
d

420
K. J. Filipski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 415–420
Table 3
Selectivity data for glucagon receptor antagonists 43–50
hGCGR Binding Ki (
l
M)a
hGLP-1 Binding Ki (
l
M)a
hGLP-1 Ki/hGCGRA Ki
hGIP Binding Ki (
l
M)a
hGIP Ki/hGCGRA Ki
43
44
45
46
47
48
49
50
0.430
0.091
0.019
0.067
0.012
0.048
0.009
0.017
21.8
16.5
10.4b
9.08
0.816
4.22
3.34b
6.62
51
4.08
9.5
10
—
29
25
80
17
55
181
547
136
68
88
371
389
0.939
NTc
1.95
0.300
3.84
0.152
0.927
a
b
c
Reported as the geometric mean of n P 2 determinations except where otherwise noted.
Reported as n=1.
NT = not tested.
clearance was observed. One compound demonstrated a dose-
dependent reduction in glucose excursion following a glucagon
challenge in rats. Notably, these analogs have significantly reduced
lipophilicity compared to previously reported series containing the
b-alanine side chain. As already observed in in vitro systems, this
hopefully will lead to better safety profiles in vivo.
Table 4
Rat pharmacokinetic parameters for compounds 44, 45, 47, and 50a
t1/2 (h)
Vdss (L/kg)
Cl (mL/min/kg)
F (%)
44
45
47
49
50
0.7
0.3
0.3
0.4
1.7
1.17
1.13
0.615
1.27
2.83
48
67
56
81
76
11
4
0.5
2
6
References and notes
a
Wistar-Han rats dosed at 1 mg/kg iv and 5 mg/kg po.
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Dog pharmacokinetic parameters for compounds 44 and 50a
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Vdss (L/kg)
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44
50
2.3
1.8
1.04
0.623
9.6
4.6
828
1870
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Figure 2. Blood glucose response following 3 lg/kg glucagon in Wistar-Han rats
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In conclusion, we have discovered a series of glucagon receptor
antagonists with reduced molecular weight and lipophilicity com-
pared to many previously reported antagonists. Both pyrazole
ethers and aminopyrazoles were found with desirable in vitro po-
tency, permeability, and solubility profiles. These compounds
showed good pharmacokinetic profiles in dog, while in rat high
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