Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes

Article abstract of DOI:10.1016/j.bmcl.2011.04.035

The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.

Full text of DOI:10.1016/j.bmcl.2011.04.035

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3290–3296
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a nortropanol derivative as a potent and orally active GPR119
agonist for type 2 diabetes
⇑
Yan Xia , Samuel Chackalamannil, William J. Greenlee, Charles Jayne, Bernard Neustadt, Andrew Stamford,
⇑
Henry Vaccaro, Xiaoying (Lucy) Xu, Hana Baker, Kim O’Neill, Morgan Woods, Brian Hawes, Tim Kowalski
Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are
described. Extensive structure–activity relationship (SAR) studies of the lead compound 20f led to the
identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist
activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose toler-
ance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent
pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays.
Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 February 2011
Revised 4 April 2011
Accepted 7 April 2011
Available online 14 April 2011
Keywords:
GPR119 agonist
Type 2 diabetes
Nortropanol
Glucose lowering
Insulin release
Diabetes is a serious illness that affects millions of people
worldwide. In the United States alone, 23.6 million children and
adults—7.8% of the population—have diabetes. Worldwide, the to-
tal number of people with diabetes is projected to rise from 171
million in 2000 to 366 million in 2030.1 As people’s living condi-
tions improve this number is ironically on the rise.2 Diabetes is di-
vided into type 1 diabetes (insulin-dependent diabetes mellitus or
juvenile diabetes) and type 2 diabetes (noninsulin-dependent dia-
betes mellitus or adult-onset diabetes) with the latter one being
more common and affecting >90% of diabetic patients. Current
therapeutic treatment for type 1 diabetes includes insulin injec-
tions or an insulin pump. For type 2 diabetes, more therapeutic
treatments are available, especially when the disease is in the early
stage. They include glucose-independent insulin secretagogues
(sulfonylureas), insulin sensitizers (biguanides (metformin) and
thiazoladinediones (Avandia, Actos)), insulin, and a relatively
new class of agents, the glucose-dependent insulin secretagogues
such as GLP-1 mimetics (Byetta, Victoza) and DPP-4 inhibitors
(Januvia). Novel diabetes medications, especially oral medications
that do not have the side effects of older ones (e.g., hypoglycemia,
weight gain) are active areas of research both in industry and in
academics to meet the needs of diabetic patients.
G protein-coupled receptor 119 (GPR119) agonists have
emerged as a promising therapeutic approach for the treatment
of type 2 diabetes.3 GPR119 was discovered recently by several
groups and has been referred to by different names such as RUP3
or glucose-dependent insulinotropic receptor (GDIR).3c It is a G
protein-coupled receptor which is selectively expressed on pancre-
atic beta cells and intestinal enteroendocrine cells. Agonists to
GPR119 stimulate glucose-dependent insulin secretion in vitro
and lower an elevated blood glucose level in vivo.4 Additionally,
they have been demonstrated to stimulate the release of the incre-
tins (glucagon-like peptide-1 (GLP-1) and gastric inhibitory poly-
peptide (GIP)).5 Numerous patents describing GPR119 agonists
have been disclosed,3 and several companies have advanced
GPR119 agonists into the clinic for the treatment of type 2 diabetes
(Ortho-McNeil/Arena (APD-668 and APD-597; both discontinued),
Sanofi-Aventis/Metabolex (SAR-260093/MBX-2982; Ph II), Glaxo-
SmithKline (GSK-1292263; Ph II), Astellas/Prosidion (PSN-821; Ph
II) and Bristol-Meyers Squibb (Ph I)).3d
In our continued effort to develop GPR119 agonists for the
treatment of diabetes,6 we became interested in the pyrimidine
derivative 1 as a lead structure (Fig. 1).7 In particular, we were
interested in bicyclic scaffolds 2–7 as replacements for the piperid-
inol scaffold in 1 as shown in Figure 1. Here we describe the out-
come of this endeavor and the discovery of
a nortropanol
⇑
Corresponding authors. Tel.: +1 908 740 3510; fax: +1 908 740 7164 (Y.X.); tel.:
derivative 36j which is a potent agonist of the GPR119 receptor
in vitro and orally active in lowering blood glucose levels in ro-
dents in vivo.
+1 732 594 0083; fax: +1 732 594 3570 (T.K.).
E-mail addresses: yan.xia@merck.com (Y. Xia), timothy.kowalski@merck.com (T.
Kowalski).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.035

Y. Xia et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3290–3296
3291
O
O
O
O
N
N
N
N
N
N
O
N
O
N
5
3
4
O
O
2
Me
Me
1
N
N
O
O
6
7
Figure 1.
HO
HO
HO
c
c
NBoc
NBoc
NBoc
a, b
O
10
12
NH
8
NBoc
HO
13
NBoc
11
NBoc
NBoc
d
e
f
+
HO
Alternatively: 14
16
15
O
OH
14
15
15:16
( = 2:1) 16
g
h
N
N
N
N
N
N
N
N
O
Cl
O
OR
20a-f
-Selectride; (d) NaBH4; (e) L-Selectride; (f) (i) p-NO2PhCO2H,
10-13, 15, 16
Cl
Cl
18
Me
Me
Me
Me
Me
19
Scheme 1. (a) (i) LiAlH4, (ii) Boc2O, DIEA; (b) Hg(OAc)2, H2O then NaBH4; (c) (i) DMSO, (COCl)2 then NEt3, (ii)
DEAD, Ph3P, (ii) NaOH, H2O; (g) 2-Methylpyridin-3-ol, K2CO3; (h) KO-t-Bu.
L
Table 1
Scheme 1 illustrates the synthesis of compounds 20a–f which
N
N
incorporates target scaffolds 2–7. We used a t-butyl carbamate
group for compounds 20a–f instead of the isopropyl carbamate
in 1 for our initial screening. Alcohols 10 and 11 were prepared
according to the published patent procedures as shown in
N
O
OR
Me
Me
-OR
Compound no.
EC50 (nM)a
Scheme 1.8 Then they were transformed to alcohols 12 and 13 by
O
a two-step sequence: a Swern oxidation followed by an L-Selectride
reduction.9 Alcohols 15 and 16 were prepared in one step from the
nortropinone 14 by NaBH4 reduction.10 Alternatively, alcohol 15
N
O
1
15
O
was obtained exclusively from 14 by an L-Selectride reduction.
Then 15 was converted to the alcohol 16 in high yield by the
Mitsunobu protocol. Alcohols 10–13, 15, and 16 were incorporated
into the final targets 20e–f as shown in Scheme 1 according to pub-
lished procedures.7
O
20a
20b
20c
558
NBoc
2580
860
O
O
Compounds 20a–f were evaluated for their abilities to activate
the human GPR119 receptor in a cell-based cAMP assay.11 The re-
sults expressed in EC50 values are shown in Table 1. Of the scaffolds
evaluated, those that maintain a 4-hydroxypiperidine structure in-
stead of 3-hydroxypiperidine gave better GPR119 activation activ-
ities (20a, 20c, 20e, and 20f vs 20b and 20d). Compound 20f,
incorporating a 3b-nortropanol scaffold, gave the best EC50 value
which is equivalent to the EC50 value of compound 1. Presumably,
compound 20f best mimics the active conformation of 1.3e
Encouraged by the potency of 20f we further explored the opti-
mization of in vitro GPR119 agonist activities based on this nortro-
panol scaffold. Various N-derivatizations of the bicyclic motif were
examined first. The Boc group in compound 20f was removed by
treatment with trifluoroacetic acid. Libraries of carbamates, sulfon-
amides, amides, ureas, and amines were prepared from the result-
NBoc
NBoc
20d
>20,000
NBoc
NBoc
O
O
20e
20f
176
18
NBoc
O
a
The standard deviations are <50%.

3292
Y. Xia et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3290–3296
Table 2a
O
O2
1. TFA
2. RCl
R
N
N
S
20f
N
N
N
N
O
N
O
O
O
O
Me
Me
F
21
21a-q
Compound no.
-R
hEC50 (nM)
h% max
mEC50 (nM)
m% max
21
82
100%
403
100%
O
O
O
O
O
20f
18
24
18
131
61
31%
72%
40%
53%
47%
300
20%
20%
12%
25%
20%
O
O
O
O
O
21a
21b
21c
21d
55
>30,000
324
10,357
CF3
O
O
O
21e
37
44%
7,573
59
33%
31%
O
O
21f
38
30
31%
35%
21g
O
O2
S
21h
21i
330
112
35%
56%
O2
S
660
63
62%
76%
CF3
O2
S
21j
>5000
24
9%
O2
S
21k
57%
O2
S
21l
32
41%
68%
53
49%
62%
O2
S
21m
112
250
CF3
O2
S
21n
21o
30
15
36%
64%
26
70
29%
69%
O2
S
O2
S
S
21p
21q
25
42
10%
10%
145
350
77%
78%
Cl
F
O2
S
a
hEC50: EC50 for human GPR119; mEC50: EC50 for mouse GPR119; h% max: magnitude of cAMP stimulation for human GPR119 expressed in% compared to the reference
GPR119 agonist 2112 which is defined to have 100% cAMP stimulation; m% max: magnitude of cAMP stimulation for mouse GPR119 expressed in% compared the reference
GPR119 agonist 2112 which is defined to have 100% cAMP stimulation. The standard deviations are <50% for EC50 and <10% for % max.
ing amine and tested for GPR119 agonist activities. We found that
carbamates and sulfonamides were more active in general than
amides, ureas, and amines. Representative examples of carbamates
and sulfonamides are shown in Table 2. The in vitro agonistic activ-
ities were evaluated by two measures: the potency measure as ex-
pressed in EC50 values in the cAMP assay and the magnitude of
agonist activity measure as expressed in % max which is a compar-
ison of the test compound to a reference GPR119 agonist 2112

Y. Xia et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3290–3296
3293
Table 3
Table 4a
Compound
no.
oGTT@3 mpk
(% of vehicle)
C1 h
(nM)
Rat AUC0–6 h
(10 mpk, nM/h)
Compound no.
hEC50 (nM)
h% max
mEC50 (nM)
m% max
28
29
30
31
32
33
34
18
>30,000
38
1150
130
918
62
14%
52
48%
78%
74%
52%
21
78%a,c
100%d
95%d
480a
193
130
20,672
175
2841
879
0
21a
21b
21k
21o
81%
29%
45%
240
710
220
87%c
2,330
89%b,c
160b
a
b
c
@1 mpk.
a
@10 mpk.
p 60.05.
p >0.05.
The standard deviations are <50% for EC50 and <10% for % max.
d
compound or vehicle dosing, prior to glucose administration, and
20 min after glucose administration. The glucose level of mice
dosed with test compound was expressed as a percentage of the
glucose level in vehicle treated mice (defined as 100%). Typically,
highly efficacious compounds in this assay gave glucose levels of
80% or lower (e.g., compound 21 in Table 3). Compounds producing
glucose levels of 95% or higher are usually not efficacious in a sta-
tistically significant way. Mouse plasma samples of drug-treated
animals were collected at 1 h post dosing and analyzed for drug
concentrations to get an estimate of the correlation between phar-
macokinetics and pharmacodynamics of test compounds. Selected
compounds were also evaluated in our rat pharmacokinetics as-
say13 to assess their oral bioavailability and potential for further
development. As shown in Table 3, carbamates 21a and 21b did
not lower blood glucose level significantly in the mouse oGTT assay
consistent with their low agonist activity (low m% max) for the
mouse GPR119 receptor. The sulfonamide 21k on the other hand
was orally active in lowering blood glucose (87% of vehicle at
3 mpk). This is consistent with the potent EC50 value (63 nM) and
high agonist activity (76% max) of 21k in mouse. It is also notewor-
thy that compound 21k had a high plasma level in mouse
(defined as 100% activation). The in vitro activities were evaluated
in two species as expressed in hEC50 and h% max for human and
mEC50 and m% max for mouse. Of the carbamates evaluated, good
potencies were observed in general as exemplified by the hEC50s of
compounds 20f, 21a, and 21b. However, the carbamates appear to
be partial agonists (except 21a) as shown by their relatively low h%
max. Moreover, they have low agonist activity for mouse GPR119
receptor as shown by their high mEC50 values or low m% max. This
made their evaluation in the mouse oGTT model difficult. The alkyl
sulfonamides, on the other hand, seem to have better agonist activ-
ity. For example, sulfonamides 21k and 21o have low EC50 values
and relatively high % max in both human and mouse GPR119 as-
says. The aromatic sulfonamides 21p and 21q have the desired
low hEC50s. However, their agonist activities were rather low as
indicated by their low h% max.
Compounds 21a, 21b, 21k and 21o were evaluated in vivo in
our mouse model of oral glucose tolerance test (oGTT). Test
compound or vehicle was orally administered to overnight-fasted
animals at 3 mg/kg. Glucose was administered to the animals
30 min post-dosing (3 g/kg po), and blood glucose levels were
measured using a hand-held glucometer (Bayer Breeze 2) prior to
(C1 h = 2.3
lM), much higher than its EC50 value in mouse. Com-
pound 21k was evaluated in a rat pharmacokinetics assay and it
CO2Me
N
b, c, d
NCO2Pri
a
Ar
Ar
f
e
NCO2Pri
Ar
NCO2Me
O
O
N
O
CO2Me
O
27
28
29
24
23
O
S
O
O
S
Ar
Ar
Ar
g
i
S
h
N
N
N
O
O
O
O
27
O
O
O
31
32
30
F
OH
j
N
N
Ar:
O
S
O
S
N
Ar
Ar
i
O
N
O
N
O
O
Me
Me
33
34
F
F
O
O2S
N
O2S
N
m
k
l
N
N
N
N
16
N
N
B(OH)2
OH
R
O
Cl
O
CF3
CF3
Me
37
38
36a-j
Me
35
Scheme 2. (a) (i) 1,1,3,3-Tetrabromopropan-2-one, ZnEt2, (ii) Zn–Cu;15 (b)
L-Selectride; (c) (i) p-NO2PhCO2H, DEAD, Ph3P, (ii) NaOH, H2O; (d) 19, KO-t-Bu; (e) (i) TMSI, (ii)
i-PrOCOCl and NEt3; (f) Pd(OAc)2, diazomethane; (g) (i) TMSI, (ii) c-PrSO2Cl and NEt3; (h) (i) 9-BBN, (ii) H2O2; (i) DAST, heat; (j) DMSO, (COCl)2 then NEt3; (k) (i) 18, NaH, (ii)
TFA, (iii) c-PrSO2Cl and NEt3; (l) ArOH, K2CO3, or ArNH2, NaH, or ArNH2, NaO-t-Bu, Pd(dba)2, BINAP; (m) H2O2.

3294
Y. Xia et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3290–3296
Table 5a
O2S
N
N
N
R
O
Me
36a-j
c
Compound no.
R
hEC50 (nM)
h% max
mEC50 (nM)
m% max
oGTTb
87%d
C1 h (nM)
Rat AUC0–6 h
N
21k
36a
24
57%
63
76%
2330
879
O
O
Me
N
2120
166
54%
89%
NA
NA
CF3
O
S
O
36b
640
88%
N
H
F
36c
36d
44
7
81%
58%
82
68
58%
74%
O
O
Cl
88%d
290
461
CN
Cl
36e
50
66%
290
44%
O
CN
N
36f
54
86
61%
59%
2,000
180
110%
80%
N
H
Me
CN
36g
N
H
F
36h
36i
36j
34
15
3
82%
81%
96%
820
220
140
110%
84%
N
H
CN
NC
NC
95%e
91%d
0
N
H
F
110%
275
2170
N
H
Cl
a
b
c
The standard deviations are <50% for EC50 and <10% for % max.
@3 mpk, po (% of vehicle).
@10 mpk, po (nM/h).
p 60.05.
d
e
p >0.05.
showed moderate plasma level with an area-under-the-curve
(AUC) from 0 to 6 h of 879 nM. The sulfoxide 21o was orally active
at a higher dose of 10 mpk (blood glucose 89% of control). Its plas-
ma level at 1 hour time point was more than two times of its EC50
value in mouse. However, in the rat pharmacokinetics assay, it did
not give any appreciable plasma level.
We further explored the optimization of potency and oral bio-
availability based on the sulfonamide 21k. The two-carbon bridge
of the nortropanol scaffold and the methylpyridinol substituent on
the pyrimidine ring were modified as shown in Scheme 2 and
Tables 4 and 5. For the structural changes on the two-carbon
bridge of the nortropanol scaffold, they were not well tolerated.

Y. Xia et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3290–3296
3295
Table 6
P450 enzyme inhibition IC50
>20
0.09 @ 10
9% @ 10
<30% @ 10
l
M for 3A4, 2D6, and 2C9 isozymes
PXR
hERG ionworks
GPCR-1
lM
lM
lM
Monkey PK, 3 mpk, 20%HPBCD
Ames
AUC0–24 h = 16,548 nM/h; Cmax = 997 nM; Tmax = 4.5 h
Negative
oGTT
Vehicle
36j (3 mpk)
AUC 0-60min
300
36j (10 mpk)
36j (30 mpk)
21 (30 mpk)
Water
14000
13000
12000
11000
10000
9000
250
200
150
100
0.4µM
0.8µM
1.4µM
*
*
12.7µM
*
39% 47%
28%
30%
-30 -20 -10
0
10 20 30 40 50 60
Time (min)
8000
Figure 2. oGTT PK/PD (dose response) of compound 36j in lean mice (10% NMP, 5% cremophor, and 20% HPbCD vehicle).
as shown in Table 6 and Figures 2 and 3. It did not produce unde-
Plasma Insulin
sired activities in our standard enzyme inhibition, enzyme induc-
tion (PXR),16 and hERG17 assays. It is highly selective for the
GPR119 receptor and inactive for ca. 40 other GPCRs in our in-
house GPCR counter-screen assay. Compound 36j showed excel-
lent monkey pharmacokinetics when dosed at 3 mpk orally with
4
3
2
1
0
a 0–24 h AUC of 16.5 lM and Tmax of 4.5 h. In the Ames assay for
carcinogenicity, compound 36j turned out to be negative.
Vehicle
36j (1mpk iv)
In a pharmacokinetic and pharmacodynamic dose-response
study in lean mice (Fig. 2), compound 36j showed a dose depen-
dent lowering of blood glucose excursion (as represented by the
excursion AUC from 0 to 60 min) with statistically significant low-
ering of 30% and 39% at 10 and 30 mpk, respectively. The plasma
concentrations of 36j increased approximately linearly (0.4, 0.8,
0
15
30
45
60
75
90
Time (minutes)
Figure 3. Compound 36j increases insulin release during hyperglycemia (300 mg/
dl) in lean, anesthetized rats.
As shown in Table 4, of the analogs synthesized (compounds
28–34), only the unsaturated-bridge compound (30) gave good
activity (low EC50s and high % max). All of the other derivatives
produced moderate to drastic reduction of activity. Changes to
the methylpyridinol portion of 21k were much more tolerated.
These compounds (36a–j) were prepared from intermediate 35
by displacement reactions under a variety of conditions as shown
in Scheme 2. The phenyl or pyridylhydroxy or amine reagents re-
quired for step l in Scheme 2 are mostly commercially available
except the trifluoromethylpyridinol reagent 38 which was pre-
pared by H2O2 oxidation of the corresponding boronic acid 37.14
Compounds 36a–j showed excellent improvement in in vitro activ-
ities as exemplified by compounds 36d, 36i, and 36j. Compound
36j in particular showed a potent human GPR119 agonist activity
with a 3 nM EC50 and 96% max. It was orally active at 3 mpk with
a 1 h plasma concentration roughly twice its mouse EC50 value. It
also had good plasma level in the rat pharmacokinetic assay. Com-
pound 36d also displayed a single digit nM hEC50 and orally active
at 3 mpk. However its plasma level in the rat pharmacokinetic as-
say was rather low. Compound 36i did not lower blood glucose le-
vel significantly orally in the mouse oGTT assay presumably due to
its low exposure in mice (C1 h = 0).
and 1.4 lM) at 3, 10, and 30 mpk although not proportionally.
Since GPR119 agonists have been reported to stimulate glucose-
dependent insulin secretion,4 we further studied the in vivo effect
of compound 36j on insulin in a rat (anesthetized) hyperglycemic
clamp model (Fig. 3). The animals were anesthetized and glucose
infusion was initiated at time 0 min. Once glucose levels reached
the target concentration of 300 mg/dl (20 min), compound 36j or
vehicle was administered intravenously (1 mpk). As shown in
Figure 3, the insulin level in the compound 36j treated arm was
significantly higher than the vehicle arm. Glucose was maintained
at 300 mg/dl throughout the study; no change in glucose infusion
rate was observed (data not shown), probably because hyperglyce-
mia was clamped at a high concentration.
In summary, we have discovered a potent and orally active
GPR119 agonist 36j incorporating a nortropanol scaffold. Com-
pound 36j is a single digit nM GPR119 agonist with high magni-
tude of agonist activity. It is orally active in lowering blood
glucose levels and was shown to increase plasma insulin levels in
a hyperglycemic model. Compound 36j also showed good to
excellent pharmacokinetic properties in rats and monkeys and no
untoward activities such as enzyme inhibition or enzyme induc-
tion. Compound 36j demonstrated an attractive in vitro and
in vivo profile for further development. The follow-up studies
and results will be reported in due course.
Compound 36j was further evaluated in a number of in vitro
and in vivo assays to assess its potential for further development

3296
Y. Xia et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3290–3296
4. Overton, H. A.; Fyfe, M. C. T.; Reynet, C. Br. J. Pharmacol. 2008, 153, S76 (suppl.
Acknowledgments
1).
5. Chu, Z.-L.; Carroll, C.; Alfonso, J.; Gutierrez, V.; He, H.; Lucman, A.; Pedraza, M.;
Mondala, H.; Gao, H.; Bagnol, D.; Chen, R.; Jones, R. M.; Behan, D. P.; Leonard, J.
Endocrinology 2008, 149, 2038.
6. Neelamkavil, S. F.; Boyle, C. D.; Chackalamannil, S.; Stamford, A. W.; Greenlee,
W. J.; Neustadt, B. R.; Hao, J.; Hawes, B.; O’Neill, K.; Baker, H.; Kowalski, T. J.
Abstracts of Papers, 239th ACS National Meeting, San Francisco, CA, United
States, March 21–25, 2010, MEDI-182.
We thank Drs. Jianshe Kong, Yang Cao, and Jesse Wong for the
preparation of intermediates used in this study.
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