Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.09.009

Through high throughput screening and subsequent hit identification and optimization, we synthesized a series of 1-arylcarbonyl-6,7- dimethoxyisoquinoline derivatives as the first reported potent and reversible GFAT inhibitors. SAR studies of this class o

Full text of DOI:10.1016/j.bmcl.2011.09.009

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6264–6269
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives
as glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitors
⇑
Yimin Qian , Mushtaq Ahmad, Shaoqing Chen, Paul Gillespie, Nam Le, Frank Mennona, Steven Mischke,
Sung-Sau So, Hong Wang, Charles Burghardt, Shahid Tannu, Karin Conde-Knape, Jarema Kochan,
David Bolin
Department of Discovery Chemistry and Metabolic Diseases, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2011
Revised 29 August 2011
Accepted 2 September 2011
Available online 10 September 2011
Through high throughput screening and subsequent hit identification and optimization, we synthesized a
series of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives as the first reported potent and reversible
GFAT inhibitors. SAR studies of this class of compounds indicated significant impact on GFAT inhibition
potency by substitutions on the A-ring and C-ring. The ketone group was found to be necessary for high
potency. Compound 28 (RO0509347) demonstrated potent GFAT inhibition (IC50 = 1 lM) with a desirable
pharmacokinetic profile in rats, and showed significant efficacy in reducing the glucose excursion in an
OGTT test in ob/ob mice.
Keywords:
Glutamine fructose-6-phosphate
amidotransferase (GFAT)
Isoquinoline derivatives
Photo cyclization
Ó 2011 Elsevier Ltd. All rights reserved.
Enzyme inhibitor
Diabetes target
Oral glucose tolerance test (OGTT)
Diabetes is characterized by peripheral insulin resistance, in-
creased glucose production and decreased insulin secretion.
Although significant progress has been achieved in the treatment
of type-2 diabetes over the last decade, the biochemical and molec-
ular mechanisms underlying insulin resistance have not yet been
clearly defined.1 The hexosamine biosynthesis pathway (HBP) has
been identified as one of the biochemical pathways that could
contribute to insulin resistance.2 The HBP end product, UDP-N-ace-
tylglucosamine (UDP-GlcNAc), is a substrate for O-linked glycosyla-
tion of serine and threonine residues on a variety of cellular proteins,
catalyzed by O-GlcNAc transferase. The first and the rate limiting
step in HBP is the conversion of fructose 6-phosphate (Fru-6-P)
and glutamine to glucosamine-6-phosphate (GlcN-6-P) and
glutamic acid, a transformation catalyzed by glutamine fructose-
6-phosphate amidotransferase (GFAT).3 Transgenic mice over
expressing GFAT demonstrate insulin resistance.4 Clinical observa-
tions indicate a connection between increased GFAT activity and
postprandial hyperglycemia, oxidative stress and diabetic complica-
tions.5–7 Therefore, we sought a small molecule GFAT inhibitor that
could provide a useful tool to study GFAT as a potential diabetes
target and to investigate the effects of the nutrient sensing HBP
pathway on insulin resistance.
There is a very limited amount of literature information regard-
ing small molecule GFAT inhibitors. Amino acid analogs incorpo-
rating functional groups capable of reacting with cysteine were
designed as glucosamine-6-phosphate synthase inhibitors. These
compounds are irreversible inhibitors (Fig. 1, compounds 1–3).8,9
The only non-amino acid small molecule GFAT inhibitor reported
in the literature is compound 4, a natural product identified as a
screening hit (IC50 = 120
l
M) reported by Monsanto scientists.10
O
O
N+
O
O
O
Br
N
N
N
O
O
O
H2N
H2N
H2N
OH
OH
OH
3
2
1
OH
O
N
N
O
O
O
O
O
N
O
O
4
5
⇑
Corresponding author. Tel.: +1 973 235 3240; fax: +1 973 235 6263.
E-mail address: yimin.qian@roche.com (Y. Qian).
Figure 1. Structures of literature GFAT inhibitors and screening hit.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.009

Y. Qian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6264–6269
6265
COOC2H5
O
O
COOC2H5
CN
COOC2H5
NH2
O
O
O
O
NH
O
O
O
CN
d
a-b
c
R
e
COOH
N
COOC2H5
N
O
COOC2H5
COOC2H5
O
O
O
O
g
O
h
f
O
N
N
O
R
O
O
R
R
R
5-7 and 11-22
Scheme 1. Synthesis of 1-arylcarbonyl-6,7-dimethoxyisoquinoline-4-carboxylic acid. (a) sodium, ethanol/toluene; (b) diethyl carbonate, 80 °C; (c) ethanol/HCl (concd), H2
(50 psi), Pd/C (cat); (d) triethylamine, aryl acetic acid, CH2Cl2, HBTU; (e) PCl5, CH2Cl2; (f) S, neat, 165 °C; (g) SeO2, EtOAc, reflux; (h) NaOH (aq).
O
H
N
O
O
a-c
d
e
O
O
O
O
N
O
O
O
O
H3CO
O
N
H3CO
O
H3CO
O
O
O
H
O
O
f-g
O
H
N
H
O
HO
O
N
H
O
O
HO
HO
H3CO
HO
h
i
j
N
N
H3CO
O
H3CO
H3CO
O
O
O
O
O
10
Scheme 2. Synthesis of 1-arylcarbonyl-6-hydroxy-7-methoxyisoquinoline-4-carboxylic acid. (a) aminoacetaldehyde dimethylacetal, trimethyl orthoformate, dichloroeth-
ane; (b) 3-methoxybenzylmagnesium chloride, ether; (c) ethyl chloroformate, K2CO3, THF/H2O; (d) 6N HCl, acetone; (e) POCl3, DMF; (f) KOH, MeOH; (g) MnO2, CH2Cl2; (h) H2,
Pd/C; (i) SeO2, EtOAc, reflux; (j) NaOCl2, NaHPO4, 2-methyl-2-butene, t-BuOH/H2O.
During high throughput screening of our compound library, we
identified 5 as a modestly potent GFAT inhibitor (IC50 = 20 M).
Herein we report follow-up studies leading to the identification
Finally, 1-arylcarbonyl-6,7-dimethoxyisoquinolines with het-
erocycles at the 4-position were prepared. Compounds 29–31 were
synthesized according to Scheme 4.11
l
of the tool GFAT inhibitor RO0509347 (compound 28).
The method of analyzing GFAT inhibition was based on the
reaction of N-acetylglucosamine 6-phosphate with p-dimethylami-
nobenzaldehyde (Ehrlich’s reagent) and determination of the opti-
cal density at 500–610 nm of the mixture relative to control
The preparation of 1-arylcarbonylisoqunoline derivatives is de-
scribed in Scheme 1.11 The desired isoquinolines were formed
through Bischler–Napieralski reaction followed by aromatization
and oxidation. Final compounds were purified by preparative HPLC
as trifluoroacetate salts with purity greater than 98%. Compounds 5–
7 and 11–22 were prepared according to this general methodology.
To prepare compound 10, a modified Pomeranz–Fritsch reac-
tion was applied to prepare the desired isoquinoline core as de-
scribed in Scheme 2.11 Compounds 8–9 were also synthesized
using this method.
Compounds 23–28 were prepared according to Scheme 3. The
starting point was the ester, which was prepared according to
Scheme 1. This ester was reduced to the corresponding alcohol
which was converted to the key benzyl chloride intermediate. The
benzyl chloride was then transformed into compounds 23, 24, and
28 via nitrile, azide, and sulfonamide intermediates, respectively.11
samples.11,12 Inhibition of both GFAT
a and GFATb were measured
in our enzyme assay, and we observed similar inhibition potency
against the two isozymes for the isoquinoline derivatives. All IC50
numbers listed in Table 1 and Table 2 were from enzyme assays
using GFATb expressed in COS cells.12
To study the SAR of the screening hit 5, we first investigated the
effect of substitution on the A- and B-rings, the ketone and the car-
boxylic acid. As illustrated in Table 1, the A-ring is very sensitive to
structural changes. Removal of either methoxy group resulted in
complete loss of GFAT inhibition activity (compare 6 with 8, 9,
and 11). De-methylation was also not tolerated (compound 10).
It appears that 6,7-dimethoxy is the optimum substitution pattern.
The carbonyl group between the B- and C-rings turned out to be

6266
Y. Qian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6264–6269
F
H
F
F
O
O
N
Cl
N
S
O
O
O
O
O
O
a-b
c-d
N
N
O
O
O
O
O
O
28
O
Cl
NH
COOH
N
O
O
O
O
O
e, d, f
g, h, i, d
N
N
O
O
O
R
R
R
24
R=3-OPri
23
R=2-F-5-OPri
Scheme 3. Synthesis of 1-arylcarbonyl-6,7-dimethoxyisoquinoline-4-acetic acid and 1-arylcarbonyl-6,7-dimethoxyisoquinoline-4-methyleneamine sulfonamide. (a) LAH,
THF; (b) CH3SO2Cl, Et3N, CH2Cl2; (c) CF3SO2NH2, K2CO3, DMF; (d) SeO2, EtOAc, reflux; (e) NaCN, EtOH/H2O, reflux; (f) HCl (aq), reflux; (g) NaN3, DMSO 50 °C; (h) H2, Pd/C; (i)
CH3COCl, Et3N, CH2Cl2.
absolutely critical for activity. Reduction of the ketone (compound
13), or the replacement of the ketone with either an amide (com-
pound 12) or a methylene group (compound 14) completely abol-
ished inhibition. On the other hand, substitution on the C-ring of 5
provided very interesting results. Deletion of the 40-methoxy group
on the C-ring improved potency by 16-fold, while deletion of the
30-methoxy group resulted in an inactive compound (compare 5
with 6 and 7). Larger alkoxy groups, such as ethoxy or isopropoxy,
slightly improved potency (compare 6 with 15 and 16). Our data
also suggested that a 30-alkoxy substitution was not absolutely
necessary for GFAT inhibition activity, although its deletion re-
sulted in 8-fold reduction in activity (compare 6 with 19 and 22).
Interestingly, substitution with di-methyl, di-chloro or di-bromo
at the 20,60-positions of C-ring gave inactive compounds (IC50
>100
M). Adding a 60-fluoro group to a 30-alkoxy compound re-
l
sulted in a compound with similar potency (compare 6 with 17
and 20). In the absence of a 30-substituent on the C-ring, 40-substi-
tution with either electron donating (compound 7) or electron
withdrawing groups (40-methylsulfone, 40-nitro, IC50 >100
abolished GFAT inhibition activity.
lM)
We next examined the 4-carboxylic acid on the B-ring. As indi-
cated in Table 2, a one-carbon extension resulted in similar po-
tency (compare 18 with 23). Furthermore, replacement of the 4-
carboxylic acid with methylene amides and sulfonamides provided
compounds with comparable potency compared to the corre-
sponding acid analogs (compounds 24–28). Incorporation of het-
O
O
H
N
NH
O
O
N
N
HO
O
O
O
O
O
a-c
d-e
N
N
O
O
O
O
O
O
30
CN
O
O
O
O
O
O
f
g
CN
H
CN
N
O
O
N
N
h
N
NH
CN
CN
O
i
O
j
O
O
N
N
O
O
N
O
O
O
O
Br
31
Scheme 4. Synthesis of 1-arylcarbonyl-6,7-dimethoxyisoquinoline derivatives with heterocycles at the 4-position. (a) LAH, THF; (b) t-butyl-N-(tert-butoxycarbonyloxy)car-
bamate, DEAD, Ph3P, THF; (c) CF3COOH, CH2Cl2; (d) ClCONCO, THF; (e) SeO2, EtOAc, reflux; (f) NaOMe, ethyl formate, ether; (g) (i) ethyl carbamate, toluene, H2SO4, reflux; (ii)
Ph2O, 230 °C; (h) POBr3, anisole, 80 °C; (i) 3-ethoxybenzaldehyde, 1,3-dimethylimidazolium iodide, NaH, DMF; (j) NaN3, NH4Cl, DMF, 120 °C.

Y. Qian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6264–6269
6267
Table 1
Inhibition of GFAT activity by isoquinoline-4-carboxylic acids
OH
N
O
R1
R2
A
B
X
C
R3
Compound
R1
R2
X
R3
IC50
20
(l
M)a
5
6
7
8
OCH3
OCH3
OCH3
H
H
OH
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
CO
CO
CO
CO
CO
CO
CO
3,4-Di-OCH3
3-OCH3
4-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3,4-Di-OCH3
3-OCH2CH3
3-OCH(CH3)2
2-F-5-OCH3
2-F-5-OCH(CH3)2
2,6-Di-F
2,6-Di-F-5-OCH3
2,6-Di-F-5-OCH(CH3)2
H
1.20 0.62 (n = 56)
>100
>100
>100
>100
>100
>100
>100
>100
0.83 0.62 (n = 7)
0.72 0.27 (n = 8)
0.87 0.28 (n = 3)
2.50
9.93 4.4 (n = 7)
0.94 0.28 (n = 3)
0.90 0.17 (n = 3)
10.0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
OCH3
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
CONH
CH(OH)
CH2
CO
CO
CO
CO
CO
CO
CO
CO
a
IC50 value is the average std from different number (n) of enzyme assay experiment.
erocycles and acid mimetics also led to compounds with similar
levels of inhibition (compounds 29–31). When compounds 19
and 28 were further studied in GFAT enzyme reaction kinetics,
they both displayed inhibition that was competitive with gluta-
conditions, the amino acid analogues 2 and 3 showed irreversible
inhibition (IC50 = 0.15 M for 2, IC50 = 0.4 M for 3).
The sulfonamide 28 was further characterized for its physico-
l
l
chemical properties (solubility 3 lg/mL at pH 6.4, logD = 2.89 at
mine, and non-competitive with fructose-6-phosphate (Ki = 0.3
lM
pH 7.2, caco-2 cellular permeability Papp = 357 ꢀ 10ꢁ7 cm/s), and
it was selected for pharmacokinetic studies in rats. As shown in Ta-
ble 3, the crystalline form of compound 28 demonstrated low
clearance and very good oral bioavailability (F%).
for compound 28). Reversibility studies indicated they were both
reversible inhibitors (data not shown). By contrast, under our assay
Encouraged by the desirable PK profile of compound 28 (Table
3), we next studied the effect of this compound on glucose homeo-
stasis in ob/ob mice. As shown in Figure 2, when fasted ob/ob mice
(female, 28 weeks old) were dosed with compound 28 (50 mg/kg,
po, aqueous suspension) at 4 h and 1 h prior to oral glucose chal-
lenge (1 g/kg), compound 28 significantly lowered the glucose
excursion (0–180 min) in the oral glucose tolerance test (OGTT).
The lowered glucose excursion by compound 28 was also observed
in OGTT of diet-induced obesity (DIO) mice (decrease of glucose
AUC >35% compared to vehicle). These data suggested that GFAT
inhibitor could provide a potential therapeutic approach for treat-
ing type-2 diabetes.
The natural product alkaloid papaverine was reported to be la-
bile to photo degradation with the formation of several side prod-
ucts, including the oxoindoloisoquinolinium salt, through a ketone
intermediate.13,14 During our studies of 1-arylcabonyl-6,7-dimeth-
oxyisoquinoline derivatives, we observed the DMSO solution of the
majority of these compounds changed color from colorless to pink
and brown when exposed to UV light. Analysis of the brown col-
ored DMSO solution by mass spectrometry suggested the existence
of an oxoindoloisoquinolinium salt formed through photo-cycliza-
Table 2
Inhibition
dimethoxyisoquinoline
of
GFAT
activity
by
R1
4-substituted
1-arylcarbonyl-6,7-
O
O
N
O
R2
Compound
R1
CH2COOH
CH2NHCOCH3
CH2NHSO2CH3
CH2NHSO2CF3
CH2NHSO2CF3
CH2NHSO2CF3
R2
IC50 (l
M)a
23
24
25
26
27
28
2-F-5-OPri
3-OPri
1.90 1.50 (n = 6)
1.10 0.53 (n = 3)
0.90 0.20 (n = 3)
0.68 0.23 (n = 6)
4.33 1.26 (n = 3)
1.00 0.65 (n = 16)
3-OPri
2-F-5-OMe
2,6-Di-F
3-OPri
O
29
3-OPri
0.82 0.10 (n = 3)
N
S
O
O
O
N
3-OPri
3-OEt
0.58 0.31 (n = 3)
0.80 0.04 (n = 2)
Table 3
30
31
N
Pharmacokinetic properties of crystalline 28 in male rats
O
N
iv dose (10 mg/kg)
T1/2 (h)
AUC (
Vd (L/kg)
po dose (50 mg/kg)
Tmax (h)
N
N
1.68
52.3
0.4
3.2
1
N
lg ꢀ h/mL)
AUC (
l
g ꢀ h/mL)
238.8
112.5
91
a
Cmax (
F (%)
lM)
IC50 value is the average std from different number (n) of enzyme assay
experiment.
CL (mL/min/kg)

6268
Y. Qian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6264–6269
Vehicle, P.O.
Compound 28 (50 mg/kg, P.O., -4 & -1 hr)
400
300
200
100
0
0
30
60
90
120
150
180
Time (min)
Vehicle. P.O.
Compound 28 (50 mg/kg, P.O., -4 & -1 hr)
12000
10000
8000
6000
4000
2000
0
*
* = p < 0.01 vs. vehicle
Figure 2. Effects of oral compound 28 on OGTT in ob/ob mice. Top figure: measured plasma glucose level during OGTT (0–180 min); Bottom figure: total glucose AUC (area
under the curve) during OGTT (0–180 min). Non-paired test p = 0.05 considered significant.
Table 4
R4
R4
Study of degradation of 1-arylcarbonyl-6,7-dimethoxyisoquinoline (1 mM) in DMSO
under UV light (2 h)
O
O
O
O
1 mM in DMSO
N+
N
R1
R2
R3
R4
m/e
Degraded
R2
Compound
UV, 2 hr
r.t
R3
16
17
18
19
28
H
F
F
F
H
H
H
H
F
OPri
OMe
OPri
H
Aa
A
A
[Mꢁ1]+
75.9%c
25.4%c
22.0%c
0%c
O
[Mꢁ19]+, no [Mꢁ1]+
[Mꢁ19]+, no [Mꢁ1]+
[M+1]+, no [Mꢁ19]+
[Mꢁ1]+
O
R3
R1
R1=H or F
R2
A
H
OPri
Bb
30.0%d
cyclized side product (M-1) or (M-F)
(m/e)=[M-1]+ or [M-19]+
parent compound M
(m/e)=[M+1]+
a
b
c
A = COOH.
B = CH2NHSO2CF3.
Analyzed by HPLC and calculated based on parent compound UV absorption
Scheme 5. Study of photo degradation of 1-arylcarbonylisoquinoline.
difference.
d
Analyzed by LC/MS.
tion as described in Scheme 5. The photo-degraded side product
was not isolated in our studies.
(m/e) as well as the percentage of degradation of the parent com-
pound from HPLC analysis are listed in Table 4.
The photo-cyclization product carries a positive charge in the
molecule, and therefore was more sensitive to mass spectrometer
detection compared to the non-cyclized form. Compounds 16–19
and 28 in DMSO solutions (1 mM) were exposed to UV light
(254 nm) for 2 h, and then analyzed by electron spray mass
spectrometry, HPLC or LC–MS. The observed major molecular ions
It is interesting to note that compound 19 did not show any
degradation when the DMSO solution was exposed to UV light (Ta-
ble 4). This clearly demonstrated that GFAT inhibition activity from
compound 19 was not due to the photo-degradation side product.
On the other hand, when the C-ring carries a 30-alkoxy group, these

Y. Qian et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6264–6269
6269
compounds were found to degrade in DMSO to varied extents fol-
lowing UV exposure (16–18 and 28, Table 4). As shown in Table 4,
fluorine substitution at the 20-position of the C-ring substantially
reduced the amount of photo-degradation (compare 16 with 17
and 18 in Table 4). Furthermore, replacement of the 4-carboxylic
acid on the B-ring with a non-acid motif also lowered photo-deg-
radation (compare 16 with 28 in Table 4). When compound 28
(1 mM) in DMSO was exposed to daylight over 24 h, no degrada-
tion was observed. Finally, when compound 28 was stored as a so-
lid over years, no photo-degradation impurity was identified.
These results suggested that the photo induced degradation was
much more significant in DMSO solution than in the solid state.
The substitution effects on photo stability (Table 4) also demon-
strated that the undesired degradation could be minimized or
eliminated for this class of compounds.
Railkar, Jiakui Li, Ying Peng and Anjula Pamidimukkala for formu-
lation and pharmacokinetic support for the in vivo studies with
compound 28.
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In summary, we have discovered a series of 1-arylcarbonyl-6,7-
dimethoxyisoquinoline derivatives as the first reported potent and
reversible GFAT inhibitors. Photo stability studies of this class of
compounds demonstrated the substitution effects on potential
photo cyclization. Compound 28 (IC50 = 1 lM) displayed good
physicochemical properties and desirable pharmacokinetic pro-
files, showed significant effects on lowering glucose excursion in
OGTT studies. Our results suggested that GFAT enzyme could be
a potential drug target for the treatment of diabetes.
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Acknowledgments
The authors would like to thank Dr. Jefferson Tilley for con-
structive discussions and reading of the manuscript and Dr. Aruna