Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4- yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1- carboxamide (BMS-742413): A potent human CGRP antagonist with superior safety profile for the treatment of mi

Article abstract of DOI:10.1016/j.bmcl.2013.04.012

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abortive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans. Herein, we report the discovery of a highly p

Full text of DOI:10.1016/j.bmcl.2013.04.012

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3157–3161
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpi-
peridin-4-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)-
piperidine-1-carboxamide (BMS-742413): A potent human CGRP
antagonist with superior safety profile for the treatment of migraine
through intranasal delivery
a,
⇑
a
b
b
b
Prasad V. Chaturvedula , Stephen E. Mercer , Sokhom S. Pin , George Thalody , Cen Xu ,
b
b
b
a
a
Charlie M. Conway , Deborah Keavy , Laura Signor , Glenn H. Cantor , Neil Mathias ,
Paul Moench , Rex Denton , Robert Macci , Richard Schartman , Valerie Whiterock ,
Carl Davis , John E. Macor , Gene M. Dubowchik
a
a
a
a
a
a
a
a
a
Department of Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA
Department of Neuroscience Discovery Biology, Bristol-Myers Squibb R&D, 5 Research Parkway, Wallingford, CT 06492, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 February 2013
Revised 1 April 2013
Accepted 4 April 2013
Available online 12 April 2013
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be efficacious as abor-
tive migraine therapeutics with the absence of cardiovascular liabilities that are associated with triptans.
Herein, we report the discovery of a highly potent CGRP receptor antagonist, BMS-742413, with the
potential to provide rapid onset of action through intranasal delivery. The compound displays excellent
aqueous solubility, oxidative stability, and toxicological profile. BMS-742413 has good intranasal bio-
availability in the rabbit and shows a robust, dose-dependent inhibition of CGRP-induced increases in
marmoset facial blood flow.
Keywords:
CGRP receptor antagonist for intranasal
delivery
Ó 2013 Elsevier Ltd. All rights reserved.
Migraine is a severe headache that is often preceded or accom-
panied by sensory symptoms such as flashes of light, blind spots,
tingling in the arms and legs, nausea, vomiting, and increased sen-
sitivity to light and sound.1 The current standard of care for the
treatment of migraine is the class of 5-HT1B/1D receptor agonists
known as the triptans.2 Triptans are direct vasoconstrictors of
blood vessels though activation of 5-HT1B receptors and are contra-
ready demonstrated anti-migraine efficacy in Phase II clinical tri-
als, This proof of concept in acute migraine has been
demonstrated with the CGRP receptor antagonists BIBN-4096BS
(olcegepant, 1, Fig. 1), telcagepant (MK-0974, Fig. 1), MK-3207
7
(Fig. 1) and BI-44370 (not shown). Efficacy of these agents was
comparable to that of the current standard of care (triptans), but
without the cardiovascular liabilities commonly seen with that
class of agents.
3
indicated in patients with hypertension or ischemic heart disease.
Thus, a migraine drug that is devoid of cardiovascular liabilities is
expected to have a significant advantage over existing agents.
Since rapid pain relief in a migraine is paramount to treatment
success, new anti-migraine agents with a more rapid onset of ac-
tion would also have a significant differentiation over the existing
oral agents. Intranasally delivered anti-migraine agents should be
able to deliver more rapid pain relief than oral agents. Thus, this
concept, coupled with the clinical success of CGRP receptor antag-
onists prompted us to identify potent CGRP receptor antagonists
that could be administered through intranasal (IN) administration8
for rapid onset of action as an alternative to our efforts discovering
4
Calcitonin gene-related peptide (CGRP) is a 37 amino acid neu-
ropeptide belonging to a family of bioactive peptides that includes
calcitonin, adrenomedullin and amylin.5 There are several poten-
tial roles for CGRP in migraine, including dilation of cranial blood
vessels, degranulation of mast cells exacerbating neurogenic
inflammation, and effects on central sensitization.6 Studies have
shown that CGRP levels are elevated during a migraine attack.
Thus, antagonism of CGRP receptors should attenuate migraine
symptoms, and in fact, four CGRP receptor antagonists have al-
9
orally active CGRP receptor antagonists.
The IN route of administration is attractive as it affords non-
invasive delivery with the likelihood for rapid onset of action.10 In
this context, we reported a high-affinity CGRP receptor antagonist
⇑
Corresponding author. Tel.: +1 203 677 6699; fax: +1 203 677 7702.
E-mail address: Prasad.Chaturvedula@bms.com (P.V. Chaturvedula).
2
(BMS-694153, Fig. 1) that incorporated a novel 7-methylindazole
0
960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.04.012

3
158
P. V. Chaturvedula et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3157–3161
NH2
H
N
O
N
F
N
N
O
F3C
N
F
H
N
N
N
N
H
O
O
O
O
HN
N
N
NH
N
O
Br
olcegepant
1
: hCGRP Ki = 0.01 nM
telcagepant
Br
OH
F
hCGRP
Ki = 0.77 nM
H
O
N
N
HN
O
H
O
O
N
N
O
N
N
O
F
NH
N
N
H
N
F
N
N
MK-3207
hCGRP Ki = 0.021 nM
H
2
: hCGRP Ki = 0.013 nM
Figure 1. Known CGRP receptor antagonists.
amino acid as a key structural moiety and a dihydroquinazolinone
as the key G-protein coupled receptor (GPCR) pharmacophore
with LDA generated the enolate which upon quenching with
2-nitrobenzadehyde provided the nitro alcohol 7 as a diastereo-
meric mixture. Reduction of the nitro group with iron in acetic acid,
followed by treatment with hydrogen chloride in dioxane provided
8
,11
(Fig. 1).
The primary challenges that initially emerged in the
development of 2 as an IN CGRP receptor antagonist were oxidative
stability of the dihydroquinazolinone in aqueous solution that was
accelerated by light, and nasal irritation and olfactory epithelial
atrophy upon IN delivery seen in rodent toxicity studies (data not
shown). In this Letter, we report the discovery of compound 3
8
,11
the desired quinolone 4. Fragments 4 and 8
were efficiently cou-
0
pled with N,N -disuccinimidyl carbonate to install the urea func-
tionality in 78% yield (Scheme 2). Saponification of the methyl
ester 9 with lithium hydroxide gave a nearly quantitative yield of
carboxylic acid 10. TBTU mediated coupling of acid with commer-
cially available 1-(1-methylpiperidin-4-yl)piperazine provided
compound 3 in excellent yield.
(
BMS-742413) as a CGRP receptor antagonist for IN administration
with greatly improved oxidative stability with diminished nasal
irritancy while retaining picomolar receptor binding potency and
excellent aqueous solubility, both necessary because of the limita-
tions of nasal delivery. Our initial efforts to modify 2 began by
replacing the oxidatively susceptible benzylic methylene group of
Compound 3 displayed concentration-dependent inhibition of
[125I]CGRP binding to the human CGRP receptor endogenously ex-
pressed in SK-N-MC cell membranes with a mean K
i
of 23 ± 2 pM.13
2
the dihydroquinazolinone in 2 with an electron-deficient sp -
Saturation binding experiments involving concentration-depen-
dent studies suggested a behavior consistent with competitive
mechanism of receptor inhibition. Functional receptor antagonism
by compound 3 was determined by measuring its ability to inhibit
CGRP-stimulated formation of cyclic AMP in SK-N-MC cells.13 The
compound was found to be full, competitive antagonist
1
2
hybridized methine in 4. The synthesis of compound 4 starts with
a Horner–Emmons reaction of N-Boc-4-piperidone with the ylide
generated from trimethylphosphonoacetate to afford tert-butyl 4-
(
2-methoxy-2-oxoethylidene)piperidine-1-carboxylate 5 in excel-
lent yield (Scheme 1). Catalytic hydrogenation mediated by palla-
dium on carbon reduced the unsaturated double bond. Treatment
of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate 6
b
(K = 22 pM). The selectivity of 3 for the CGRP receptor over other
receptors in the calcitonin receptor family was assessed using
O
a
OMe
b
OMe
BocN
O
BocN
BocN
O N
O
O
O
P
OMe
OMe
5
6
MeO
2
c
O
H
N
H
N
O
e
d
MeO
O
O
HCl
HN
BocN
OH
BocN
OH NO2
4
7
2
Scheme 1. Reagents and conditions: (a) NaH, DMF, 92%; (b) H , 10% Pd on carbon, MeOH, 94%; (c) LDA, THF, 94%; (d) Fe–HOAc, 77%; and (e) HCl in dioxane, EtOAc then
crystallize from 5% water in isopropanol.

P. V. Chaturvedula et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3157–3161
3159
H
N
O
O
O
H
N
H
N
NH2
O
N
MeO
a
MeO
b
+
O
N
N
H
HN
8
4
9
N
N
H
H
H
N
O
N
O
O
O
H
N
c
H
N
N
N
HO
N
O
N
O
N
N
NH
N
1
0
3
N
N
N
H
N
H
2 3
Scheme 2. Reagents and conditions: (a) succinimidylcarbonate, THF, 78%; (b) LiOH in THF/MeOH/H O, 96%; and (c) TBTU, Et N, DMF, 85%.
radioligand binding assays. Compound 3 displayed greater than
assessment of CGRP receptor antagonists.8,9 In brief, marmosets
were anesthetized and laser Doppler facial blood flow was in-
creased by four separate intravenous (IV) administrations of
1
0,000 fold selectivity for CGRP over adrenomedullin receptors 1
13
and 2, calcitonin, and amylin receptors 1 and 3.
Compound 3 was tested in two ex vivo assays measuring (i)
reversal of CGRP-induced dilation (reversal protocol), or (ii) shift
of CGRP-dose response (Schild analysis). The antagonist 3 showed
potent and full reversal of CGRP-induced dilation of ex vivo human
intracranial arteries (EC50 = 880 ± 50 pM), and produced a parallel
rightward shift of the CGRP concentration–response curve in
h
a
CGRP (10
105 min). The first delivery provided a baseline control response
to h CGRP, and the three subsequent deliveries reflected post-dose
l
g/kg) delivered at 45 min intervals (ꢀ30, 15, 60 and
a
effects where the CGRP receptor antagonist was delivered subcuta-
neously (SC) at 0 min. When compared to pre-dose vehicle control
(ꢀ30 min), Compound 3 (0.03 mg/kg, SC; 0 min) produced a strong
48% inhibition at 15 min post-dose. Robust 80% and 70% inhibitions
were observed at 60 and 105 min post-dose, respectively, (Fig. 3).
The total plasma levels during the 15–105 min post-dose time per-
iod ranged from 25 to 31 nM (Fig. 3).
In vitro safety profiling of 3 suggested a low potential for hepa-
tic, cardiovascular or genotoxic liabilities. Compound 3 was well
tolerated acutely in rats given 660 mg/kg SC, providing very high
exposure multiples (both Cmax and AUC) of the projected effica-
ex vivo human intracranial arteries (K
compared favorably with the in vitro binding (K
functional (K = 22 pM) assay results. Compound 3 did not demon-
strate active contraction of ex vivo human coronary artery up to
M. In contrast, sumatriptan (Imitrex™) showed progressive,
concentration-dependent contraction with EC50 = 280 ± 50 nM
Fig. 2). The absence of active constriction by antagonist 3 is a
b
= 91 pM).13 These results
= 23 pM) and
i
b
1
0
l
(
reflection of the different mechanism of action for CGRP receptor
antagonists: that of an anti-dilatory effect (returning dilated ves-
sels to normal), and demonstrating that this class of agents (CGRP
receptor antagonists) will likely be free from the cardiovascular lia-
bilities seen with the triptans.
1
4
cious human intranasal dose. In a 10-day SC rat safety study,
compound 3 was well tolerated with no evidence of systemic tox-
icity (0.3, 3, 10, and 30 mg/kg/day; Fsc = 82%). In a seven-day rat
safety IN irritancy study, there were no findings when compound
Compound 3 was tested in the novel non-invasive marmoset
recovery model established in our laboratories for in vivo efficacy
3 was dosed at 75 and 175 mg/mL (12.5 lL/nostril in succinate buf-
fer), the optimal allometrically scaled volume for rats. In contrast,
our previous IN compound 2 showed significant irritation at both
dose levels (Fig. 4). At higher concentrations, P75 mg/mL, and
Sumatriptan
BMS-742413
higher volumes, P25 lL/nostril, compound 3 caused dose-related
8
6
4
2
0
0
0
0
0
Laser Doppler Facial Blood Flow
Plasma
1
1
25
00
40
3
3
2
5
0
5
75
50
25
0
*
20
1
1
5
0
5
0
*
*
-
9
-8
-7
-6
-5
1
0
10
10
10
10
-30
15
60
105
Time (min)
Figure 2. Effect of sumatriptan and compound 3 (BMS-742413) on ex vivo human
coronary arteries.
Figure 3. Efficacy in marmoset facial blood flow model.

3
160
P. V. Chaturvedula et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3157–3161
Figure 4. Nasal cavity and respiratory epithelium of rats dosed intranasally for 7 days with (A, C) compound 2, or (B, D) compound 3. In A and B, the rats were dosed at 75 mg/
mL, 12.5
l
L/nostril (total dose 1.875 mg), and in C and D, the rats were dosed at 175 mg/mL, 12.5
l
L/nostril (total dose 4.375 mg). In A (compound 2), the respiratory
⁄
⁄
epithelium is atrophied ( ). In B (compound 3), there are no lesions. In C (compound 2), the lumina are nearly occluded by exudate (red ), and many neutrophils infiltrate the
lamina propria. In D (higher magnification than C; compound 3), a few neutrophils infiltrate the lamina propria.
lesions in the nasal olfactory and respiratory epithelium, character-
ized primarily by epithelial atrophy. At 175 mg/mL (100 L/nos-
tril), compound 3 caused inflammation, erosion and ulceration,
and single-cell necrosis of the olfactory epithelium and minimal
to slight neutrophilic inflammation and single-cell necrosis of the
respiratory epithelium. Notably however, at each dose above
Compound 3 showed no time-dependent CYP3A4 inhibition. The
antagonist 3 did not prolong action potential duration in Purkinje
fibers and had little effect on other action potential parameters
l
up to 30
hERG patch clamp assay (9.5% and 22% inhibition at 10 and
30 M, respectively), suggesting a low potential for QT related
electrocardiographic changes. Compound 3 at 10 M showed no
lM. The compound showed only weak activity in the
l
P75 mg/mL and volume above P25
l
L/nostril, the incidence and
l
severity of lesions was markedly less with compound 3 than with
compound 2.
significant potential for off-target liabilities in a broad panel of
receptor and ion channel binding and enzyme activity assays.
In summary, we have identified compound 3 (BMS-742413), a
potent CGRP antagonist with much improved oxidative stability
in comparison with our previous lead (2), by incorporating a quin-
Compound 3 possessed two protonatable nitrogens as part of
the N-methylpiperidinyl-piperazine amide that resulted in a high
2
polar surface area (116.18 Å ). Consequently, binding of 3 to serum
proteins in vitro was low over a range of species including human
olinone GPCR privileged moiety and 7-methylindazole D-amino
1
5
(f
u
= 37%). A 40 mg/mL solution of 3 (succinate buffer pH 6, 40 °C)
acid as key structural motifs. BMS-742413 (3) had outstanding
aqueous solubility, suitable for IN delivery, and good intranasal
bioavailability with peak concentrations occurring within 15–
20 min. The compound reverses CGRP-induced dilation of ex vivo
human intracranial arteries. The compound displayed excellent
activity in a marmoset facial blood flow model, as well as favorable
in vivo safety margins for both systemic and IN toxicity. BMS-
742412 represents a significant clinical opportunity for a nasally
delivered CGRP receptor antagonist. Additional reports on the pro-
gress of BMS-742413 will be made in due course.
showed only 0.3% degradation after 3 months. In addition, the
crystalline compound possessed phenomenal aqueous solubility
easily sufficient to support nasal delivery (105 mg/ml at pH = 8.5
and >300 mg/mL at lower pH).
Compound 3 exhibited poor permeability in Caco-2 cells
(
16 nm/s (A–B); 16 nm/s (B–A)) and PAMPA assays, and showed
minimal oral bioavailability in cynomolgus monkey (F = 0.3%) or
mouse (F = 1.4%). In contrast, IN absorption of compound 3 in the
rabbit was rapid and efficient. The time to reach peak concentra-
tions (Tmax) occurred within 15–20 min at all doses studied. The
absolute bioavailability of 3 was found to be dependent on the con-
centration of the dosing solution with bioavailability increasing on
going from a 10 mg/ml (13%) to a 100 mg/ml solution (30%), with
References and notes
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3
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.
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.
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Compound 3 demonstrated a low probability of drug–drug
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a variety of CYPs (CYP3A4 (BFC) >40
lM, (BzRes) 24
l
M; CYP2D6
M).
>
40 M; CYP2C9 >40 M; CYP2C19 >40
l
l
lM; CYP1A2 >40 l

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pre-contracted with 10 mM KCl (to mimic endogenous tone), fully dilated with
1 nM CGRP. Concentration–response curves to CGRP antagonists were
performed by the cumulative addition of CGRP antagonist on fully dilated
vessels.
5
564; (e) Hewitt, D. J.; Martin, V.; Lipton, R. B.; Brandes, J.; Ceesay, P.; Gottwald,
(b) The EC50 values (concentration of compounds that elicit 50% reversal) were
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antagonists (n = 4) vessels for each compound.
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9
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studies and calculations which went into this projection will be published
separately in due course.
(a) Luo, G.; Chen, L.; Conway, C. M.; Denton, R.; Keavy, D.; Gulianello, M.;
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enantiomeric excess (ee) was determined to be >99.9% (conditions: Chiralpak
AD column, 4.6 ꢁ 250 mm, 10
30% ethanol; at 1.0 mL/min. for 45 min. The retention times were 18.7 min for
R and 28.1 min for S). 1H NMR (500 MHz, DMSO-d
) d ppm 13.01 (s, 1H), 11.76
lm; eluent: 70% (0.05% diethylamine)/heptane/
(
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6
2
(s, 1H), 7.96 (s, 1H), 7.62 (d, J = 7.10 Hz, 1H), 7.60 (s, 1H), 7.42 (m, 1H), 7.36 (s,
1H), 7.26 (d, J = 8.25 Hz, 1H), 7.14 (m, 1H), 7.00 (s, 1H), 6.69 (d, J = 8.25 Hz, 1H),
4.78 (q, J = 7.79 Hz, 1H), 4.14 (d, J = 12.37 Hz, 2 H), 3.54 (dd, J = 9.16, 4.58 Hz,
1H), 3.24 (m, 1H), 3.11 (m, 1H), 2.97 (m, 1H), 2.89 (m, 2 H), 2.69 (m, 4 H), 2.32
(m, 1H), 2.21 (m, 1H), 2.07 (m, 4 H), 1.95 (t, J = 8.25 Hz, 1H), 1.87 (m, J = 11.28,
11.28, 3.55, 3.44 Hz, 1H), 1.76 (t, J = 12.03 Hz, 2 H), 1.68 (t, J = 11.11Hz, 2 H),
1
1
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2
012, 22, 4723; (b) Han, X.; Jiang, X.-J.; Civiello, R. L.; Degnan, A. P.;
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1.53 (t, J = 8.25 Hz, 1H), 1.32 (m, 4 H), 1.16 (m, 2 H); 13C NMR (DMSO-d
6
) d
16.80, 27.30, 30.51, 30.51, 30.67, 35.50, 38.04, 41.74, 44.00, 44.16, 45.35, 45.78,
48.14, 48.39, 51.45, 54.76, 54.76, 60.61, 114.53, 117.79, 119.29, 119.34, 121.57,
122.78, 127.46, 127.79, 129.29, 129.79, 133.31, 133.72, 136.98, 137.41, 139.12,
3
R. L.; Pendri, Y.; Nielsen, B.; Nugent, W. A.; Parker, W. L., Quinlan, S.; Reising, N.;
Remy, B.; Sausker, J.; Wang, X. Org. Process Res. Dev. 2012, 16, 1953.
2. Rudolf, K.; Eberlein, W.; Engel, W.; Pieper, H.; Doods, H.; Hallermayer, G.;
Entzeroth, M.; Wienen, W. U. S. Patent 6,344,449, 2002.
3. For experimental procedures used to measure
inhibition, functional antagonism (EC50), ex vivo efficacy in intracranial
+
156.50, 161.50, 170.42. Accurate mass analysis: m/z 639.3770, [MH] ,
1
1
d = ꢀ0.2 ppm. Optical rotation: ꢀ27.36° @ 589 nm, concentration = 4.71 mg/
mL in methanol.
[
125I]CGRP binding, CYP