Calcitonin gene-related peptide (CGRP) receptor antagonists: Novel aspartates and succinates

Article abstract of DOI:10.1016/j.bmcl.2012.02.066

Novel aspartate and succinate CGRP full antagonists were identified through core modification of a potent lead CGRP antagonist, BMS-694153. While aspartates were much less active and had a flat SAR, some of the succinates were very potent CGRP full antago

Full text of DOI:10.1016/j.bmcl.2012.02.066

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2912–2916
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Calcitonin gene-related peptide (CGRP) receptor antagonists: Novel
aspartates and succinates
⇑
Guanglin Luo , Ling Chen, Sokhom S. Pin, Cen Xu, Charles M. Conway, John E. Macor, Gene M. Dubowchik
Molecular Sciences and Candidate Optimization, Neuroscience Discovery Biology, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 3 March 2012
Novel aspartate and succinate CGRP full antagonists were identified through core modification of a potent
lead CGRP antagonist, BMS-694153. While aspartates were much less active and had a flat SAR, some of
the succinates were very potent CGRP full antagonists and matched the potency of BMS-694153. The
most potency resides in the S enantiomer as demonstrated through an asymmetric synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
CGRP antagonist
Migraine
Migraine is a common and disabling illness that affects approx-
imately 12% of the adult population in Western society.1 The dila-
tion of cranial blood vessels was hypothesized to be associated
with migraine headache 70 years ago.2 The current standard of
treatment, the 5-HT1B/1D agonists (triptans), act primarily through
constriction of intracranial arteries.3 However, these nonselective
vasoconstrictors are also associated with significant cardiovascular
side effects resulting in their contraindication in patients with
hypertension or ischemic heart disease.4 The calcitonin gene-
related peptide (CGRP), a 37 amino acid neuropeptide, is an
extremely potent vasodilator and has been implicated in the
pathogenesis of migraine.5 Therefore, CGRP receptor antagonist is
an attractive therapeutic target for the treatment of migraine.6
Clinical proof of concept for this has recently been achieved with
intravenous administration of the potent antagonist BIBN-4096
(olcegepant) with alleviation of pain in migraneurs.7 Other small-
molecule CGRP receptor antagonists with clinical benefit have also
been reported.8
F
H
N
O
N
O
H
N
N
N
O
N
N
N
H
BMS-694153
hCGRP Ki = 0.013 nM
O
O
N
N
N
N
HN
O
O
N
A recent publication from our laboratory disclosed a potent,
indazole-based, CGRP receptor antagonist, BMS-694153, (Fig. 1)
with rapid and efficient intranasal exposure.9 However, with poor
intrinsic permeability, BMS-694153 did not have significant oral
bioavailability in either the cynomolgus monkey or rat. Further
SAR studies have been carried out aiming at modifying the core
structure to modify the chemotype, and potentially increase oral
bioavailability. Herein, we report the SAR around core aspartate
and succinate derivatives of BMS-694153 (Fig. 1).
Our initial work on aspartates focused on derivatization of the
primary amino group of 5, which was easily prepared from
commercially available aspartic acid 1 (Scheme 1). Thus, mono-
protected acid 1 was coupled with 3-(piperidin-4-yl)-3,4-dihydro-
Aspartates
Succinates
Figure 1. Novel aspartate and succinate derivatives.
quinazolin-2(1H)-one9 using a published procedure to afford the
amide 2.10 Hydrogenation of 2 afforded the acid 3, which reacted
with 4-piperidinopiperidine to give the diamide 4. TFA-mediated
deprotection afforded the primary amine 5. Using parallel synthe-
ses, a variety of secondary amines, amides, carbamates, and ureas
(6) were prepared through standard 96-well library synthesis.11
All target compounds were tested in a competitive [125I]CGRP
binding assay (hCGRP IC50) and selected examples were tested
for their antagonist activity (cAMP IC50) following previously pub-
lished procedures.9 The majority of the library compounds were
active CGRP antagonists with binding and functional IC50 values
⇑
Corresponding author.
E-mail address: guanglin.luo@bms.com (G. Luo).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.02.066

G. Luo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2912–2916
2913
Table 1
H
O
N
hCGRP binding and functional data for compounds 6a–k
O
Bn
N
Compds
R
hCGRP IC50, nMa
cAMP IC50, nMa
OH
a
O
O
HN
O
tBOC
Bn
N
O
6a
700
N
HN
O
tBOC
1
2
NH
6b
380
N
N
O
X =
b
NH
N
6c
130
300
H
N
H
N
O
OH
6d
4500
N
N
O
O
c
N
O
N
F
X
HO
6e
430
O
HN
HN
O
tBOC
3
4
F
H
N
tBOC
d
O
6f
590
280
O
O
N
O
O
O
H
N
N
O
X
e
6g
5
NH2
O
N
O
N
N
Cl
6h
6i
97
36
45
N
H
HN
O
Cl
N
O
R
6
Cl
Scheme 1. Reagents and conditions: (a) 3-(diethoxyphosphoryloxy)-1,2,3-benzo-
triazin-4(3H)-one, 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one, Et3N,
CH2Cl2, 65%; (b) Pd/C, H2, EtOAc/MeOH (1/1), 93%; (c) same as (a) with 4-
piperidinopiperidine, 71%; (d) TFA, CH2Cl2, 98%; (e) 6a–d: aldehyde or ketone,
sodium triacetoxyborohydride, CH2Cl2; 6e–g: acyl chlorides, Et3N, ClCH2CH2Cl; 6h–
6k: isocyanates, ClCH2CH2Cl.
NH
NH
NH
Cl
F
O
O
O
6j
below 1 lM. Representative examples from different libraries are
listed in Table 1. The most potent compounds were all halogenated
aryl ureas (6h–k). However, these compounds generally had poor
solubility and poor Caco-2 cell permeability and were not further
evaluated.
6k
100
Cl
a
Values are means of at least two experiments.
We were also interested in N-arylated analogs that provided a
more direct comparison to BMS-694153. A number of these (6l,
n–q, Table 2) were made using direct nucleophilic aromatic substi-
tutions of corresponding reactive aromatic halides with amine 5.12
Direct Buchwald type reactions gave only limited success.13 There-
fore, a racemic synthesis of N-arylated aspartate 7 was devel-
oped.14 Orthogonally protected 714 was successively hydrolyzed
and amidated to give the desired N-aryl aspartyl amides 6s–u
(Scheme 2).15
As shown in Table 2, a small number of these N-aryl aspartates
demonstrated binding and functional potency below 100 nM. Un-
like BMS-694153, 6q was not made more potent by the presence
of a 7-methyl group. Similarly disappointing was that the presence
of a hydrogen bond donor (i.e., 6q–s) failed to have a dramatic ef-
fect on potency.7,9 Overall, the SAR around the aspartate core was
rather flat and did not track with that of the ureidoamide core of
BMS-694153. For example, compared with 6s, the corresponding
ureidoamide compound has a hCGRP binding IC50 of 0.52 nM.9 In
BMS-694153, the indazole group is free to rotate, while in the
aspartic acid analogs, the amine NH likely forms a hydrogen bond
with the right amide, restricting the substituent’s rotation (Fig. 2).
Thus, the conformation of the aspartate core is likely very different
from the ureidoamide core as in BMS-694153. The expansion from
the ureidoamide core in BMS-694153 to the aspartic acid core was
deleterious to CGRP antagonist activity.
11 following a base-promoted Stobbe condensation reaction17 to
afford isomeric mixture 12.18 It was remarkable that under these
conditions, the less-substituted ester was specifically hydrolyzed
to the mono-acid 12. After hydrogenation, the saturated mono-acid
13 was generated. Amide coupling to give 14 was achieved under
standard conditions.10 Hydrolysis of 14 afforded the acid 15, which
led to the bis-amide 16 through a second amide coupling (Scheme
3).
Table 3 summarizes hCGRP binding and cAMP functional data
for succinate analogs 16a–n. Most succinates showed very potent
activity. Unlike the aspartate series, 7-methyl substitution of the
indazole core dramatically increased potency (16a versus 16l and
16g vs 16m). This ‘7-methyl effect’ was comparable to the 30-fold
potency increase seen in our previously reported urea series, with
16b being essentially equipotent with its ureidoamide analog.9
Thus, the change from the amino acid core in the ureido series
(exemplified by BMS-694153)9 to the succinate core resulted in
structurally different, but similarly active CGRP antagonists.
An asymmetric route to compounds 16 is shown in Scheme 4.
Condensation of aldehyde 1716 with malonic acid afforded the
unsaturated acid, which upon hydrogenation and ester formation,
generated the methyl ester 18. Regioselective protection of
indazole16 18 afforded 19 in excellent yield. After hydrolysis, the
(R)-4-benzyl-2-oxazolidinone derivative 20 was prepared, and
asymmetric alkylation of 20 following a published procedure
afforded 21.19 Hydrolysis of the chiral auxiliary followed by amide
Synthesis of racemic succinates is outlined in Scheme 3. Com-
mercially available indazole-5-aldehyde or previously synthesized
7-methylindazole-5-aldehyde16 reacted with dimethyl succinate

2914
G. Luo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2912–2916
Table 2
O
H
N
O
hCGRP binding and functional data for compounds 6l–v
Compds
Ar
hCGRP IC50, nMa
cAMP IC50, nMa
O
N
O
H
Cl
N
Ureidoamide core
Aspartate core
6l
98
46
N
N
Figure 2. Possible conformational difference between the ureidoamide core and
aspartate core.
N
6m
6n
1400
32
Cl
32
99
O2N
O
X
Cl
N
O
H
N
OH
a
MeO
X
N
OMe
O
MeO
N
O
6o
250
O
OHC
N
O
NH
Me
11
N
H
(X = H or Me)
N
12
N
N
Me
OH
R1
NO2
6p
6q
80
73
O
X
O
N
b
c
d
NH2
N
MeO
X
N
N
NH
O
N
N
N
H
N
120
N
H
Me
13
14
R1
R1
O
O
6r
6s
180
170
59
NH
N
R2
N
N
HO
X
N
NH
O
O
230
e
N
N
N
H
N
H
15
X
16a-n
6t
890
120
220
N
Scheme 3. Reagents and conditions: (a) KOtBu, tBuOH, 60–95%; (b) Pd/C/H2,
MeOH/EtOAc (1/1); (c) 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one,
4-substituted piperidine, Et3N, CH2Cl2; (d) LiOH, THF; (e) Same as (c).
Br
6u
6v
Table 3
hCGRP binding and functional data for compounds 16a–n
R1
a
Values are means of at least two experiments.
O
R2
N
N
O
N
O
O
N
H
O
OH
O
a
b
O
O
X
HN
O
HN
O
X
R2
R1
hCGRP IC50, nMa cAMP IC50, nMa
Ar
Ar
7
8
O
N
H
N
H
N
O
O
NH
16a
Me
0.33
0.70
N
N
O
O
N
c
N
N
O
O
N
HO
N
N
N
NH
NH
HN
O
HN
O
10
16b
16c
Me
Me
0.074
0.18
0.068
0.089
Ar
Ar
9
H
N
O
O
N
F
O
d
N
N
O
HN
O
HN
N
Ar
NH
16d
Me
0.34
0.35
6s-u
Scheme 2. Reagentsandconditions: (a)TFA, CH2Cl2;(b)3-(diethoxyphosphoryloxy)-
1,2,3-benzotriazin-4(3H)-one, 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one,
Et3N, CH2Cl2; (c) LiOH, THF; (d) identical to (b) with 4-piperidinopiperidine.

G. Luo et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2912–2916
2915
O
Table 3 (continued)
CHO
X
R2
R1
hCGRP IC50, nMa cAMP IC50, nMa
OMe
O
a, b, c
d
N
O
N
N
N
H
N
Me
N
O
NH
N
H
16e
Me
0.15
0.049
18
17
Me
N
O
O
OMe
SEM
N
O
NH
NH
16f
Me
Me
0.30
3.2
0.12
5.8
g
SEM
N
e, f
N
Ph
N
O
N
O
Me
19
Me
20
16g
O
O
O
O
O
O
O
O
O
N
N
N
O
O
h, i
O
NH
O
16h
16i
Me
5.9
2.7
8.8
2.0
SEM
N
Ph
SEM N
N
N
O
N
Me
Me
R1
NH
21
22
Me Me
O
j, k
N
N
N
O
O
O
NH
16j
Me
Me
H
H
H
19
34
N
N
(S)-16
H
Me
O
N
NH
Scheme 4. Reagents and conditions: (a) malonic acid, piperidine, pyridine, 110 °C;
(b) Pd/C/H2, MeOH/EtOAc (1/1); (c) HCl (4 N in dioxane), MeOH, 81% for 3 steps; (d)
SEMCl, N,N-dicyclohexylmethylamine, THF, 95%; (e) LiOH, THF/water (2/1); (f) (1)
pivaloyl chloride, iPr2Net, THF, (2) (R)-4-benzyl-2-oxazolidinone, LiCl, 59%; (g) LDA,
tert-Butyl 2-bromo-acetate, THF, 46%; (h) LiOH, H2O2, THF/water (1/1); (i) 3-
(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, 4-piperidino-piperidine,
Et3N, CH2Cl2; (j) HCl (4 N in dioxane), THF; (k) same as (i) with different 4-
substituted piperidines.
16k
16l
3.7
6.9
O
N
O
NH
15
53
O
N
O
NH
16m
16n
H
87
320
O
Table 4
hCGRP binding and functional activity for chiral 16b and 16c
O
O
Compd
hCGRP IC50, nMa
cAMP IC50, nMa
O
O
NH
H
460
(S)-16b
(R)-16b
(S)-16c
(R)-16c
0.060
11
0.20
6.7
0.019
11
0.082
4.6
a
Values are means of at least two experiments.
a
Values are means of at least two experiments.
formation produced 22. After acidic deprotection of the tert-butyl
ester and another amide formation, the desired chiral product
(S)-16 was obtained.20
CGRP antagonists with activity similar to analogs in the amino acid
series.9 The more active chiral configuration of our succinate deriv-
atives was determined through defined asymmetric synthesis. Fur-
ther work carried out to improve oral exposure will be reported in
due course.
Binding affinity and antagonist activity of the selected chiral
compounds 16b and 16c are listed in Table 4. The S enantiomers
are more potent than their R counterparts. While these succinate
analogs had generally good metabolic stability, attractive CYP inhi-
bition profiles (data not shown) and hCGRP receptor potency com-
parable to their urea analogs, they did not show observable oral
exposure in rats, nor did they possess aqueous solubility that
would make them suitable for intranasal delivery (data not
shown). Caco-2 permeability in the succinate series did show a
modest improvement over the ureidoamides, but the compounds
were still clearly too polar for efficient bilayer permeability.
In conclusion, novel aspartate and succinate CGRP antagonists
and analogs to BMS-694153 were identified, and their SAR with re-
spect to hCGRP binding and function studied. While SAR was gen-
erally flat in the aspartate series, potent CGRP antagonists were
seen in the succinate series. In fact, the succinate series produced
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5
[2-
(dicyclohexylphosphino)-20-(N,N-dimethylamino)biphenyl, Pd2(dba)3, CsCO3,