Design and synthesis of conformationally constrained tri-substituted ureas as potent antagonists of the human glucagon receptor

Article abstract of DOI:10.1016/j.bmcl.2006.11.014

A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC₅₀ of 4.0 nM a

Full text of DOI:10.1016/j.bmcl.2006.11.014

Bioorganic & Medicinal Chemistry Letters 17 (2007) 587–592
Design and synthesis of conformationally constrained
tri-substituted ureas as potent antagonists of the
human glucagon receptor
Rui Liang,a,* Lauren Abrardo,a Edward J. Brady,c Mari Rios Candelore,b Victor Ding,b
Richard Saperstein,c Laurie M. Tota,b Michael Wright,b Steve Mock,a
Constantin Tamvakopolous,a Sharon Tong,a Song Zheng,a
Bei B. Zhang,b James R. Tataa and Emma R. Parmeea
aDepartment of Basic Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
bDepartment of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
cDepartment of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Received 22 September 2006; revised 2 November 2006; accepted 6 November 2006
Available online 10 November 2006
Abstract—A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor
antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was
shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Com-
pound 4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as
3 mg/kg.
Ó 2006 Elsevier Ltd. All rights reserved.
Glucagon is a 29-amino acid peptide hormone secreted
by the a-cells of the pancreatic islets. In the liver, gluca-
gon binding to its G protein coupled receptor (GPCR)
stimulates gluconeogenesis and glycogenolysis that re-
sult in increased plasma glucose levels. Together with
insulin, that acts to decrease plasma glucose levels, glu-
cagon plays a pivotal role in maintaining blood glucose
homeostasis.1 Type 2 diabetics are insulin resistant and
show elevated postprandial glucagon levels resulting in
impaired glucose homeostasis.2 It has been demonstrat-
ed that intravenous administration of potent peptide
glucagon antagonists, anti-glucagon antibodies, and
more recently, antisense oligonucleotides against the
glucagon receptor significantly decreases blood glucose
levels in diabetic animal models.3 These studies suggest
that a glucagon receptor antagonist could decrease
hepatic glucose output and improve glucose control in
diabetic patients. It has also been shown that a small
molecule glucagon receptor antagonist can effectively
block the glucose response to a glucagon challenge in
healthy humans.4 Therefore, glucagon receptor antago-
nism is being pursued as a promising approach to treat
type 2 diabetes.
Several classes of small molecule antagonists of the hu-
man glucagon receptor have been disclosed.5,6 Among
them, a class of tri-substituted ureas was reported as
small molecule antagonists of the glucagon receptor.6
These are exemplified by compounds 1a and 1b that
showed a potent binding IC50 and moderate functional
activity under our assay conditions (Fig. 1).7 These
antagonists have a characteristic acid moiety, such as
b-alanine or amino tetrazole, attached to the benzyl
group in the para position. As part of our investigation
of conformationally constrained analogues of 1,8 the
benzylic carbon was cyclized to either the carbonyl oxy-
gen or the phenyl ring (Fig. 1). Analogues in which the
benzylic position was attached to the carbonyl oxygen (2
and 3) were moderately potent antagonists of glucagon
receptor (binding IC50 ꢀ 130–630 nM).9 In contrast,
Keywords: Glucagon; Glucagon receptor; Glucagon receptor antago-
nist; Diabetes; Hyperglycemia; Glucose.
*
Corresponding author. Tel.: +1 732 594 9448; fax: +1 732 594
9473; e-mail: rui_liang@merck.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.014

588
R. Liang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 587–592
F3CO
Scheme 1 describes the synthesis of antagonists 4–6. Ke-
O
tone esters 8, 12, and 14 were prepared by carbonylation
of either 5-bromo-1-indanone 7 or the corresponding
triflates of phenols 11 and 13.10 Reductive amination
of ketones 8, 12, and 14 with 4-tert-butylcyclohexyl-
amine using NaBH4 and catalytic Ti(O-iPr)4 gave 4:1
trans/cis mixtures of racemic secondary amines, which
can be easily separated by silica gel chromatography.
The trans amines were further treated with 4-trifluoro-
methoxyphenyl isocyanate to give tri-substituted ureas.
The compounds were resolved at this stage on chiral
HPLC to give optically pure enantiomers. Saponifica-
tion, followed by amide coupling with the b-alanine
derivatives or 5-amino tetrazole and if necessary depro-
tection, gave the final compounds 4–6. For comparison
of the effect of stereochemistry on biological activity,
amine 10 was derivatized to give the final urea 4-cis
using analogous conditions.
N
H
N
H
N
A
O
tBu
O
N
N
1b, A =
OH
1a, A =
NH
N
1a, IC50 = 21 nM (binding), 144 nM (cAMP)
1b, IC50 = 3.2 nM (binding), 46 nM (cAMP)
F3CO
O
(CH2)n
N
N
H
N
A
O
2, n = 1
3, n = 2
tBu
F3CO
O (CH2)n
N
X
Biological activity of compounds 4–6 was initially mea-
sured by the inhibition of binding of [125I]glucagon to
the human glucagon receptor expressed in CHO cell
membranes. Functional activity was measured by the
inhibition of glucagon-induced cAMP accumulation in
hGCGR transfected CHO cells (cAMP IC50, Table
1).7 Significant differentiation in activities was observed
between enantiomers, and the potent enantiomers were
comparable to or showed improvement in activity over
the parent compounds 1a and 1b. The binding activity
of enantiomers E1 (prepared from the first-eluting urea
enantiomers) ranged from 0.5 to 5 nM and was up to
800-fold more potent than that of enantiomers E2.
Enantiomers E1 were also more potent functional
antagonists. Consistent with data on compounds 1a
and 1b, amino tetrazole derivatives 4b, 5b, and 6b were
more potent than the corresponding b-alanine deriva-
N
H
H
N
A
O
4, X = CH2 , n =1
5, X = CH2, n =2
6, X = O, n =2
tBu
Figure 1. Tri-substituted ureas (1a and 1b) are glucagon receptor
antagonists. Arrow indicates the position for conformation constraint
by tethering to the carbonyl oxygen or the adjacent phenyl ring.
significantly improved in vitro results were seen for ana-
logues in which the benzylic position was attached to the
phenyl ring (4–6, binding IC50’s ꢀ 0.5–5 nM). Here we
report the synthesis of analogues in this series and their
biological activity as glucagon receptor antagonists.
A
OC4H9
OC4H9
HN
HN
b
a
O
OC4H9
O
O
+
O
Br
O
7
8
c-e
tBu
9
tBu
10
c-e
F3CO
F3CO
O
O
H
H
N
N
N
H
N
A
N
N
A
H
O
O
4-cis
4
tBu
tBu
B
F3CO
O
HO
X
CH3O2C
X
O
X
f
b-e
a, A =
OH
N
H
N
H
N
N
O
N
O
A
b, A =
NH
O
N
5 X = CH2
6 X = O
12 X = CH2
14 X = O
11 X = CH2
13 X = O
tBu
Scheme 1. Reagents and conditions: (a) CO, PdCl2(PPh3)2, DIEA, n-BuOH, 115 °C (79%); (b) 4-tert-butylcyclohexylamine, Ti(O-iPr)4, NaBH4,
EtOH, rt (65% trans, 16% cis); (c) 4-(trifluoromethoxy)phenyl isocyanate, THF, 0 °C (91%); (d) chiral HPLC (ChiralPak AD column, 10–15% IPA in
n-Heptane); (e) 1—LiOH, H2O/THF/MeOH; 2—ANH2, HOBt, EDC, DIEA, DMF, rt; 3—1:1 TFA/CH2Cl2, rt (60–84%); (f) 1—Tf2O, Et3N,
DMAP, CH2Cl2, À78 °C to rt (61–93%); 2—CO, Pd(OAc)2, dppf, Et3N, DMF, MeOH, 50 °C (85–98%).

R. Liang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 587–592
589
Table 1. Binding and functional activity (IC50) of the ring constrained urea antagonists 4–6 of the human glucagon receptor and the related human
GIP receptor
F3CO
O
(CH2)n
N
X
O
N
H
H
N
OH
a, A =
b, A =
N
N
A
NH
N
O
tBu
Compound
n
X
Binding IC50, nM (n) E1/E2
cAMP IC50, nM (n) E1/E2
hGIP cAMP IC50, nM (n) E1
4a
4b
1
1
1
1
2
2
2
2
CH2
CH2
CH2
CH2
CH2
CH2
O
4.1 1.1 (2)/1085
2.31 0.03 (2)/359
3.8 1.1 (2)/3384
1.01 0.01 (2)/216
3.4 1.3 (2)/340
0.5/148
33 21 (8)/489
15/2888
132 38 (4)
296
603
4a-cis
4b-cis
5a
46/NDa
18 9 (3)/795
54 23 (2)/2173
11 6 (2)/1052
44 17 (3)/1013
39 22 (4)/1454
435
171
5b
6a
178 123 (2)
217 80 (2)
117 54 (2)
4.8/218
0.5/76
6b
O
All compounds were tested as pure enantiomers. E1, compounds 4–6 prepared from the first to elute urea enantiomers; E2, compounds 4–6 prepared
from the second to elute urea enantiomers.
a Not determined.
F3CO
tives 4a, 5a, and 6a. The most potent analogue, E1 of 5b,
O
(CH2)n
N
O
exhibited a binding IC50 of 0.5 nM and a functional IC50
of 11 nM, which was ca. 4-fold more potent than the
parent compound 1b.
A
N
N
H
H
15, n =1
16, n =2
O
Activity of compounds 4–6 toward the related human
GIP and GLP-1 receptors was also examined.11 As the
primary action of both GIP and GLP-1 is the stimula-
tion of glucose-dependent insulin secretion, antagonism
of these receptors should be minimized. Compounds 4–6
showed little activity against the hGLP-1 receptor, with
functional IC50’s > 10 lM in the cAMP accumulation
assay. However, they all had potent hGIP activity
(cAMP IC50’s = 0.1–0.6 lM). Compounds (5 and 6)
from the 6-membered ring series showed equally potent
activity against hGIP. In the 5-membered ring series,
compound 4a with a b-alanine side chain has potent
hGIP activity, while compound 4b with a tetrazole was
marginally less potent against hGIP. The stereochemis-
try of the tert-butylcyclohexyl ring has some influence
on the selectivity against hGIP receptor. Compound
4a-cis was equally potent against glucagon receptor as
the trans compound 4a, but it displayed slightly better
selectivity against hGIP than 4a. Since hGIP activity
of all these compounds was similar, further SAR studies
focused on the more easily available trans isomer of the
5-membered ring series.
OH
a, A =
b, A =
tBu
N
N
NH
N
F3CO
O
(CH2)n
N
N
H
17, n =1
18, n =2
O
NH
tBu
A
Figure 2. Analogues with the acid side chain at different position on
the phenyl ring.
phenyl (19) or 4-cyclohexyl-phenyl group (20) on the
tertiary nitrogen of the urea both led to significant
decreases in both binding and cAMP activity. This sug-
gested that tert-butyl-cyclohexyl group was preferred
on the internal nitrogen over the substituted aromatic
rings in the ring-constrained urea.
Some exploration of factors influencing the selectivity
over hGIP receptor of compound 4 was investigated
through removal of the external nitrogen of the urea
(Fig. 3 and Table 3).13 Replacement of the external
nitrogen with a methylene group (21a–21b) resulted in
loss of activity against the glucagon receptor, while the
selectivity over hGIP did not improve. Directly attach-
ing the phenyl moiety to the central carbonyl group as
in 22a–22b also led to substantial loss of activity against
glucagon receptor. Further exploration through replace-
ment of the 4-trifluorophenyl group with 3,5-di-substi-
tuted phenyl groups (23–24) improved selectivity over
hGIP. 3,5-Dichlorophenyl derivatives 23a and 23b
not only retained good in vitro potency but also had
Analogues 15–18 (Fig. 2) which have the carboxylic acid
or amino tetrazole at either meta-position to the benzylic
urea moiety were also evaluated. They were consider-
ably less active (binding IC50’s of 200–1200 nM) as com-
pared to the compounds 4 which have the acid moieties
at the para-position to the benzylic urea.
We then attempted to improve the potency of com-
pounds 4a and 4b by varying the hydrophobic substitu-
ents on the internal nitrogen of the urea (Table 2).12
Replacement of the tert-butyl-cyclohexyl with 4-CF3O-

590
R. Liang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 587–592
Table 2. Binding and functional activity (IC50) of the ring constrained urea antagonists 19–20 of the human glucagon receptor
O
CF3O
O
OH
H
N
a, A =
b, A =
N
N
A
N
N
NH
N
H
Ar
O
Compound
Ar
Binding IC50, nM (n)
cAMP IC50, nM (n)
19a
19b
20a
20b
4-CF3O-Ph
4-CF3O-Ph
820
62
Inactive
3434
4-Cyclohexyl-Ph
4-Cyclohexyl-Ph
68 32 (2)
22 8 (2)
189 28 (2)
85 35 (3)
All compounds were tested as pure enantiomers. Data shown are from the more potent enantiomers.
F3CO
O
excellent functional selectivity (>100- and >500-fold,
respectively) over hGIP.
H
N
N
A
A
O
Having identified potent and selective glucagon receptor
antagonists, we wanted to evaluate the pharmacokinetic
profiles of these ring constrained compounds 4–6 (Table
4).14 Carboxylic acids 4a, 5a, and 6a displayed similar
pharmacokinetic properties in mice, showing low clear-
ance in vivo, half-life of 2–6 h, and moderate bioavail-
ability. Interestingly, the tetrazole derivative 5b was
markedly different. It had a very low AUC and poor
oral bioavailability.
21
t-Bu
O
H
N
N
F3CO
O
X
22
t-Bu
O
H
N
X
N
H
N
The antagonists 4–6a, 4–6b, and 23a were tested for
their ability to block glucagon-induced hyperglycemic
response in vivo using transgenic mice that exclusively
express a functional human glucagon receptor.15 Oral
administration of the antagonists was followed 60 min
later by an intraperitoneal injection of glucagon. All
compounds inhibited the hyperglycemic response at
30.0 mg/kg in 24 min except compound 5b, most likely
due to its poor pharmacokinetic properties. Compound
4a was selected for a dose titration in the assay, and a
A
O
23 X = Cl
24 X = CF3
t-Bu
O
N
N
b, A =
OH
a, A =
NH
N
Figure 3. Analogues in which one of the urea nitrogens was either
replaced by a methylene group (21) or deleted (22).
Table 3. Binding and functional activity (IC50) of the ring constrained urea antagonists 21–24 of the human glucagon receptor
Compound
Binding IC50, nM (n)
cAMP IC50, nM (n)
GIP cAMP IC50, nM (n)
21a
21b
22a
22b
23a
23b
24a
24b
18 10 (3)
4.8 3.1 (3)
130 21 (2)
49 31 (2)
10 2 (2)
500 278 (3)
67 12 (2)
286
118
2778 897 (2)
1467 275 (2)
NDa
610
11
5.9
46
61
1279
3525
2023
4256
4.9 0.2 (2)
28 13 (2)
7.6 3.0 (2)
All compounds were tested as pure enantiomers. Data shown are from the more potent enantiomers.
a Not determined.
Table 4. Pharmacokinetic profiles of selected human glucagon receptor antagonists dosed in mice (n = 3 mice/route of administration)a
Compound
CLp (mL/min/kg)
Vdss (L/kg)
t1/2 (h)
AUCN (PO) (lM h/dose)
Cmax (lM)
F%
4a
5a
5b
6a
9
9
1.6
0.9
1.4
1.4
5.6
2.5
8.0
3.4
0.56
0.35
0.09
0.34
0.13
0.09
0.04
0.06
17
10
6.4
13
1.4
15
a Compounds were dosed at 1.0 mpk IV and 2.0 mpk PO formulated with a 5:10:85 mixture of DMSO, Tween 80, and water.

R. Liang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 587–592
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significant response was observed at doses as low as
3 mg/kg. The glucose corrections to vehicle controls
were 51%, 59%, and 122% at 3, 10, and 30 mg/kg,
respectively.
Finally, compound 4a was evaluated for its ability to
lower non-fasting blood glucose in transgenic mice
which have been placed on a high fat diet for 13 weeks
to induce moderate hyperglycemia.16 The initial glucose
levels were about 170 mg/dL in the diabetic mice and
about 110 mg/dL in the lean mice. Administration of
compound 4a as an admixture in the chow to the diabet-
ic mice gave significant correction of the glucose levels to
lean mouse control levels at 3 mg/kg by day 3 (Fig. 4).
Most notable, full glucose correction to lean levels was
achieved with 10 mg/kg by day 3 and maintained out
to day 10.
In summary, we have discovered a series of structurally
novel compounds, which are potent and selective gluca-
gon receptor antagonists. For example, one of the most
potent compounds 23b has an IC50 of 5.9 nM in
glucagon-stimulated cAMP accumulation assay with
>500-fold selectivity over hGIP. Significantly, one repre-
sentative compound 4a from this series has an accept-
able pharmacokinetic profile in the mice and
suppressed a glucagon-stimulated increase of plasma
glucose levels in transgenic mice. In the same transgenic
mice compound 4a was also efficacious in correcting
hyperglycemia induced by a high fat diet at doses as
low as 3.0 mg/kg.
These data reaffirm the findings that small molecule
antagonists of the human glucagon receptor may have
the potential to control hepatic glucose production
which is exacerbated in type II diabetics. Further work
on related series of compounds from these laboratories
will be reported in the near future.
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