Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic modification of a novel azepinone lead

Article abstract of DOI:10.1016/j.bmcl.2021.128077

In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhib

Full text of DOI:10.1016/j.bmcl.2021.128077

Bioorg. Med. Chem. Lett. 43 (2021) 128077
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Calcitonin gene-related peptide (CGRP) receptor antagonists: Heterocyclic
modification of a novel azepinone lead
,
b
,
,
,c
Guanglin Luoa *, Xiang-Jun Jianga, Ling Chena b, Charles M. Conwaya
,
Michael Gulianelloa d, Walter Kosticha e, Deborah Keavya , Laura J. Signora, Ping Chena
,
,
,
,
f
,b
Carl Davisa g, Valerie J. Whiterocka, Richard Schartmana h, Kimberly A. Widmanna,
,
,
John E. Macora , Gene M. Dubowchika
,
i
,c
a Bristol-Myers Squibb, Wallingford, CT 06492, United States
b Bristol Myers Squibb, Lawrenceville, NJ 08543, United States
c Biohaven Pharmaceuticals Inc., New Haven, CT 06510, United States
d Sanofi, Framingham, MA 01701, United States
e National Multiple Sclerosis Society, New York, NY 10017, United States
f Medtronic, North Haven, CT 06473, United States
g Amgen, Inc. Thousand Oaks, CA 91320, United States
h Preformulation Solutions, LLC, North Ridgeville, OH 44039, United States
i Sanofi, Waltham, MA 02451, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series
of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-
dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a
series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable
oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially
reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset
facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability
generally remained low, emphasizing the challenges we and others encountered in discovering clinical devel-
opment candidates for this difficult Class B GPCR target.
CGRP receptor antagonist
Imidazolone
Time-dependent CYP3A4 inhibition
Migraine
Migraine, is a common and disabling condition, affecting approxi-
mately 12% of the adult population in the western world.1 The nonse-
lective 5-HT1B/1D agonists (“triptans”) have been widely used for the
acute treatment of migraine, however these have undesirable active
vasoconstrictive properties and are contraindicated in patients with
uncontrolled hypertension or cardiovascular disease.2 Approximately
2.6 million Americans with migraine have had a cardiovascular event,
condition or procedure that limits the utility of triptans,3 highlighting
the need for new treatments. Although the precise mechanisms under-
lying the initial triggering event(s) in migraine are not fully understood,
great strides have been made in understanding migraine pathophysi-
ology and centers around the trigeminovascular system release of the
neuromodulator calcitonin gene-related peptide (CGRP).4 Therefore, a
CGRP receptor antagonist is an attractive therapeutic target for the
treatment of migraine.5 Importantly, blockade of CGRP signaling is not
associated with active vasoconstriction providing new treatment options
for patients with unmet needs.6 Initial clinical proof of concept was
achieved in the acute treatment of migraine with intravenous adminis-
tration of the high affinity CGRP receptor antagonist BIBN 4096 BS
(olcegepant) showing alleviation of pain without an unwanted cardio-
vascular signal.7 Subsequently, clinical development of two orally
bioavailable antagonists, MK-0974 (telcagepant) and MK-3207 showed
anti-migraine efficacy in clinical trials, but their development was dis-
continued due to liver safety concerns.8 Recently, two oral small mole-
cule CGRP receptor antagonists, Ubrelvy™ (ubrogepant)9 and Nurtec
ODT™ (rimegepant)10 were approved for the acute treatment of
migraine. In addition, four injectable monoclonal antibodies, one
against the CGRP receptor and three against CGRP itself, have been
* Corresponding author. Tel.: +1 6092524946.
E-mail address: guanglin.luo@bms.com (G. Luo).
https://doi.org/10.1016/j.bmcl.2021.128077
Received 22 February 2021; Received in revised form 19 April 2021; Accepted 25 April 2021
Available online 29 April 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

G. Luo et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128077
around the indazole of 1 to address this issue (Fig. 1). Specifically, we
wanted to replace the pyrazole portion of the indazole ring with other
heterocycles. Since the indazole NH in 1 has been shown to be critical for
high-affinity CGRP receptor binding affinity, we decided to retain a
hydrogen bond donor as shown in the middle structure (Fig. 1). To ac-
cess these heterocycles, we envisoned a critical key intermediate, aniline
2.
Successful preparation of intermediate 2 is outlined in Scheme 1,
which involved two diferent approaches to key intermediate 8. In the
first approach reduction of commercial nitro compound 3 afforded the
aniline 4, which was treated with ICl to obtain the iodide 5 in good yield.
Mono-Boc protection, however, went exclusively to the primary alcohol
to generate 6. Treatment with excess Boc2O yielded bis-Boc protected
product 7, which afforded a mixture of the desired alcohol 8 and com-
pound 6 after attempted selective deprotection. Compound 6, in the
presence of a catalytic amount of DMAP, could be completely converted
to the more thermodynamically stable 8 in refluxing THF. Alternatvely,
a second route to the key intermediate 8 was developed starting with
benzoic acid 9. Ester formation of 10 followed by iodide formation of 11
were achieved in good yields. Mono-Boc protection of the aniline 11 was
not feasible and bis-Boc protected interemdiate 12 was obtained in very
good yield. Reduction of the ester group to the alcohol by DIBAL,
however, led to partial deprotection, generating both 13 and the desired
alcohol 8. Compound 13 could be converted to 8 by treatment with
K2CO3 in MeOH with heating. The alcohol 8 was then protected as the
acetate to afford intermediate 14, which after Heck coupling with ita-
conic acid diethyl ester, afforded intermediate 15 in excellent yield.
Using previously established conditions,13 chiral reduction was
Fig. 1. Azepinone CGRP receptor antagonist 1, proposed heterocyclic
replacement and the key intermediate 2.
approved for migraine prevention.11 None of these six agents have
shown a liver safety signal which indicates that the early Merck expe-
riences were compound-specific effects and not CGRP-mediated. Most
recently, rimegepant and atogepant have demonstrated efficacy in the
preventive treatment of migraine, with rimegepant being the only
molecule to show efficacy in both acute and preventive treatment of
migraine.12 These data highlight the ongoing importance of these novel
oral treatments for migraine.
A recent publication from our laboratories disclosed a high-affinity
indazole-containing azepinone CGRP receptor antagonist 1 (Fig. 1)
that demonstrated good oral exposure and activity in a marmoset
pharmacodynamic assay.13 However, the compound had potent, time
dependent cytochrom P450 isoform 3A4 (CYP3A4) inhibition. Herein,
we report focused structure activity relationship (SAR) campaign
Scheme 1. Reagents and conditions: (a) Fe, AcOH/EtOH (2/1), 95 ◦C, 2 h, 61%: (b) ICl, Na2CO3, MeOH, rt, 2 h, 100% (crude); (c) Boc2O (1.05 equiv.), DMAP (cat.),
THF, 75 ◦C, 4 h; (d) Boc2O (2.1 equiv.), DMAP (cat.), THF, 75 ◦C, 6 h; (e) K2CO3, MeOH/H2O (4/1), rt, 72 h, 6 (59%) and 8 (38%); (f) DMAP (0.1 equiv.), THF, 75 ◦C,
24 h, 100% (crude); (g) Trimethyl orthoformate, H2SO4, MeOH, 60 ◦C, 28 h, 90%; (h) I2, Ag2SO4, EtOH, rt, 2 h; (i) Boc2O (2.4 equiv.), DMAP (cat.), THF, 75 ◦C, 24 h,
89% for two steps; (j) DIBAL-H, THF, ꢀ 78 ◦C, 2 h; (k) K2CO3, MeOH, 70 ◦C, 2 h; (l) Ac2O, DMAP (cat.), CH2Cl2, rt, 2 h; (m) itaconic acid diethyl ester, PdOAc2,
tetrabutylammonium chloride hydrate, Et3N, DMF, 50 ◦C, 88% for three steps; (n) (ꢀ )-1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I)
tetrafluoroborate (2.8 mol%), CH2Cl2, H2 (35 psi), rt, 96 h, 96% (crude); (o) MgO, MeOH, rt, 24 h, 100% (crude); (p) MnO2, CH2Cl2, 50 ◦C, 4 h, 100% (crude); (q)
2,2,2-trifluoroethaneamine, NaBH3CN, AcOH, MeOH, rt, 18 h, 88% (crude); (r) AcOH, toluene, 120 ◦C, 17 h, 64% from 15; (s) TFA, CH2Cl2, rt, 5 h, 89%.
2

G. Luo et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128077
Scheme 2. Reagents and conditions: (a) 2,3,5,6-tetrabromo-4-methyl-4-nitro-
cyclohexa-2,5-dienone, TFA, rt, 2 h, 52%; (b) SnCl2, EtOH, 70 ◦C, 2 h, 80%;
(c) phosgene, CH2Cl2, 1 h; (d) LiOH, THF, 48 h; (e) 3-(piperidin-4-yl)-4,5-
dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, Hunig’s base, 3-(diethyox-
yphosphoryloxy)-1,2,3-benzo-triazin-4(3)-one (DEPBT), CH2Cl2, DMF, rt, 18 h,
77% for 3 steps.
achieved to afford 16 in very good yield. Acetate was removed by hy-
drolysis with ester exchanged to afford alcohol 17, which was converted
to secondary amine 19 after generation of the aldehyde 18. Cyclization
proceeded smoothly to generate the azepinone 20 in good yield, which
afforded the desired intermediate 2 after Boc deprotection.
Synthesis of the unsubstituted imidazolone derivative 25a was ach-
ieved as shown in Scheme 2. Aniline 2 was nitrated following reported
protocols14 to afford intermediate 21, which after SnCl2 reduction,
generated bis-aniline 22. Phosgene treatment afforded the imidazolone
derivative 23, which after hydrolysis and 3-(diethyoxyphosphoryloxy)-
1,2,3-benzo-triazin-4(3)-one (DEPBT)-mediated amide formation reac-
tion15 using previously reported amide 3-(piperidin-4-yl)-4,5-dihydro-
1H-benzo[d][1,3]diazepin-2(3H)-one13, afforded the desired imidazo-
lone derivative 25a in good yield.
Scheme 3. Reagents and conditions: (a) I2, Ag2SO4, EtOH, rt, 1 h, 91%; (b)
phosgene, CH2Cl2, rt, 30 min–5 h, concentrated to dryness and redissolved in
CH2Cl2, methylamine (27a), 2,2,2-trifluoroethylamine (27b), or ethylamine
(27c), rt, 18–72 h; (c) CuI, 1,10-phenanthroline, Cs2CO3, DME, 80 ◦C, 16 h,
49% (28a), 79% (28b), 53% (28c); (d) LiOH, THF, rt, 16 h–24 h; (e) 3-
For the synthesis of substituted imidazolone derivatives a different
route was developed as shown in Scheme 3. Starting with 2, iodination
in the presence of Ag2SO4 afforded the iodide 26 in good yield. For-
mation of ureas 27a-c was achieved through sequential treatment of 26
with phosgene, followed by reaction with various amines. Intra-
molecular closure of the substituted imidazolone rings was efficiently
achieved by CuI catalysis using 1,10-phenanthroline as the ligand, a
protocol adopted from previously reported amination conditions.16 This
transformation represented a new method of preparing specifically
substituted imidazolones, and subsequently a similar condition (CuI/
DBU) using high temperature microwave heating was reported.17 The
desired products 25b-d were prepared after ester hydrolysis and amide
formation reactions similar to those described for 25a. Products 25e and
25f were prepared from 29a and 29b, respectively, using previously
reported piperidine-containing G-protein coupled receptor (GPCR)
privileged components.13
(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one,
Hunig’s
base, DEPBT, CH2Cl2, DMF, rt, 18 h, 81% for 2 steps (25b), 48 h, 83% for 2
steps (25c), 70% for 2 steps (25d).
ester, giving acid 34. Compound 35 was then formed through amide
formation. The triazole ring was formed by NaNO2 oxidation of 22 to 36,
which was converted to the triazole 38 after ester hydrolysis and amide
formation.
Scheme 6 shows the synthesis of various indole derivatives. Starting
from the iodide 26, Sonogashira coupling with TMS-acetylene afforded
39, which led to acetylene intermediate 40 after TBAF deprotection.
Indole 41 was formed by gold catalysis,18 and was converted to the
indole product 43a after hydrolysis and amidation. Intermediate 41
could be further derivatized to cyanoindole 44 by known cyanation
conditions.19 After hydrolysis, the cyanoindole acid 45 was converted to
either 43b or 43c using the two known piperidine derivatives. For
synthesis of 43c, hydrolysis of 44 led to formation of a primary amide
side product from nitrile hydrolysis, resulting in the additional forma-
tion of 43d after the coupling reaction and careful separation.
A difluoroindanone derivative 49 was also prepared (Scheme 7).
Starting with the indole 41, oxidation by CrO3 afforded the ketone 46.20
The ketone was converted to the corresponding difluoro intermediate 47
by DAST treatment. Hydrolysis of either 46 or 47 by LiOH resulted in
opening of the indanone ring.21 On the other hand, hydrolysis of 47 was
An oxazolidinone derivative 33 was prepared from the iodide in-
termediate 26 (Scheme 4). Methyl ether formation was achieved in the
presence of CuI/1,10-phenanthroline, albeit in low yield. The high re-
action temperature required also resulted in ester hydrolysis, affording
the acid 30. The ether in 30 was demethylated by BBr3 to afford amino
phenol 31, which was converted to the oxazolidinone intermediate 32
by phosgene treatment. Amide formation furnished 33 in good yield.
Syntheses of the imidazole (35) and triazole (38) derivatives were
achieved as shown in Scheme 5. The imidazole ring was formed by
heating 22 with formic acid and HCl, also resulting in hydrolysis of the
3

G. Luo et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128077
Scheme 4. Reagents and conditions: (a) CuI, 1,10-phenanthroline, Cs2CO3,
MeOH, 110 ◦C (microwave), 24 h, 27%; (b) BBr3, CH2Cl2, rt, 21 h; (c) phosgene,
Hunig’s base, CH2Cl2, 24 h; (d) 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2
(3H)-one, Hunig’s base, DEPBT, CH2Cl2, rt, 72 h, 42% for 3 steps.
Scheme 6. Reagents and conditions: (a) (trimethylsilyl)acetylene,
PdCl2(PPh3)2, CuI, Et3N, THF, 50 ◦C, 20 h, 59%; (b) TBAF, THF, rt, 1.5 h, 100%;
(c) NaAuCl4⋅2H2O, EtOH, rt, 18 h, 62%; (d) LiOH, THF/dioxane, rt, 48 h; (e) 3-
(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one,
Hunig’s
base, DEPBT, CH2Cl2, DMF, rt, 18 h, 71% (43a) for 2 steps, 83% (43bfor 2
steps; (f) chlorosulfonyl isocyanate, DMF, MeCN, 0 ◦C–rt, 2 h; (g) 1-(piperidin-
4-yl)-1H-imidazo[4,5,b]pyridin-2(3H)-one, Hunig’s base, DEPBT, CH2Cl2, DMF,
rt, 18 h, 19% (43c) and 30% (43d) for 2 steps.
The compounds described here were all high-affinity hCGRP recep-
tor antagonists possessing subnanomolar activity. In particular, the
imidazolone derivatives 25a-f achieved low double-digit picomolar
binding affinity. Functional activities (cAMP IC50) were tested for imi-
dazolones 25b-d and were 0.060 nM, 0.12 nM, and 0.090 nM, respec-
tively. Unsubstituted imidazolone 25a, imidazolones with
azabenzimidazolone GPCR-privileged components (25e-f) demon-
strated good microsomal stability but showed poor oral exposure,
possibly due to high polarity. Imidazolones 25b-d had reasonable
metabolic stability and oral exposure. Compound 49a possessed the best
oral exposure despite modest rat microsomal stability. Compound 49b,
having the more polar azabenzimidazolone GPCR-privileged compo-
nent, showed comparatively poor oral exposure, demonstrating the
difficult balance needed to be achieved with these chemotypes to ach-
ieve good oral bioavailability. Other heterocycle derivatives generally
had unacceptable metabolic stability, low oral exposure or other issues.
Several compounds were tested for in vitro CYP3A4 time dependent
inhibition after 30 min incubation. Values for imidazoles 25b and 25c
(IC50 = 8.1 µM and 8.4 µM, respectively), were greatly improved over
lead azepinone 1 (IC50 = 0.1 µM). Compound 49b was found to have no
Scheme 5. Reagents and conditions: (a) formic acid, HCl, 100 ◦C (microwave),
10 h; (b) 1-(piperidin-4-yl)-1H-imidazo[4,5,b]pyridin-2(3H)-one, Hunig’s base,
DEPBT, DMF, CH2Cl2, rt, 18 h, 55% for 2 steps (35), 76% for 3 steps (38; (c)
NaNO2, AcOH/H2O (3/1), rt, 1 h; (d) LiOH, THF, rt, 72 h.
achieved by using bis(tributyltin)oxide in refluxing toluene22 to afford
the intact acid 48, with subsequent formation of 49a after amide for-
mation. Product 49b was prepared in the same manner.
All compounds prepared were tested in a human CGRP receptor
binding assay (Ki), in competition with [125I]CGRP, and selected com-
pounds were tested for antagonist activity (cAMP IC50) in a whole-cell
assay following previously published protocols.23 All compounds
tested for functional activity were found to be full antagonists of the
human CGRP receptor (hCGRP). The hCGRP Ki values are summarized
in Table 1, along with single-point liver microsomal stabilities in three
species. In addition, Cmax values from a coarse rat pharmacokinetic (PK)
study (10 mg/kg, PO) for selected compounds are also listed in Table 1.
4

G. Luo et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128077
Scheme 7. Reagents and conditions: (a) CrO3, acetone/AcOH/H2O (1/5/1.5),
rt, 4 h, 39% from 41; (b) DAST, CH2Cl2, rt, 72 h; (c) bis(tributyltin)oxide,
toluene, 80 ◦C, 36 h; (d) 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]dia-
zepin-2(3H)-one, Hunig’s base, DEPBT, CH2Cl2, DMF, rt, 4 h, 42% for 2 steps;
(e) 1-(piperidin-4-yl)-1H-imidazo[4,5,b]pyridin-2(3H)-one, Hunig’s base,
DEPBT, CH2Cl2, DMF, rt, 66 h, 60% for 3 steps.
Table 1
Selected data for the products.
Compound
hCGRP Kia (nM)
Microsomal stability (%)b
(H/R/M)
Cmax (nM)c
(coarse rat PK)
25a
25b
25c
25d
25e
25f
33
0.019 (±0.010)
0.015 (±0.008)
0.020 (±0.006)
0.014 (±0.003)
0.043 (±0.008)
0.026 (±0.009)
0.12 (±0.05)
60/41/71
36/35/75
58/54/87
44/22/59
73/56/100
90/90/41
49/64/63
26/7/24
3
96
270
230
11
3
Fig. 2. Marmoset laser Doppler blood flow assay. Each marmoset received 4 iv
injections of hαCGRP, designed to mimic waves of CGRP release during severe
36
NT
15
NT
NT
NT
NT
480
4
migraine, delivered at ꢀ 30 min (baseline), and +15, +60 and +105 min rela-
35
0.17 (±0.05)
tive to compound (0 min).
38
0.44 (±0.04)
62/90/64
0.9/0.8/1.6
38/11/26
40/40/7
43a
43b
43c
43d
49a
49b
0.85 (±0.04)
0.06 (±0.04)
increases in marmoset facial blood flow upon sc dosing (only 7 mg/kg
dose is shown in Fig. 2). As compared to predose vehicle control (ꢀ 30
min), strong inhibition (>50%) of CGRP-induced effects on facial blood
flow was observed with 7 mg/kg of 25b at all time points (15, 60, and
105 min postdose test times). Total plasma levels of 25b were above 170
and 510 nM (3.9–11.8 nM free with fu = 2.3%) and all times were
associated with strong in vivo efficacy (>50 inhibition). Even at 3 mg/kg
of 25b, strong efficacy (up to 79%) was seen for total plasma levels of
25b above 40–200 nM (data not shown). For 25c, the strong inhibition
was observed at 60 and 105 min post-dose test times (65–84%) and total
plasma levels of 25c were above 80 and 210 nM (0.7–1.9 nM free with
fu = 0.9%). Imidazolone 25d was also tested in this assay and was
similar to 25c with the peak efficacy of 67% (not shown). For 49b,
around 50% inhibition was observed at all time points (47–56%) with
slightly stronger inhibition at the 105 min postdose test time (56%). The
total plasma levels of 49b were above 140–490 nM (7.4–26.3 nM free
with fu = 5.4%).
0.060 (±0.002)
0.40 (±0.30)
80/80/70
22/35/8.1
91/82/28
0.069 (±0.014)
0.13 (±0.07)
a
Values are the mean of at least three experiments.
b
Percent remaining after 10 min incubation in liver microsomes at 0.5 M (H
= human, R = rat, M = monkey).
c
Dosed at 10 mg/kg PO in 80%PEG400/10%DMAC/10%TW80. NT = Not
tested.
observable time dependent CYP3A4 inhibition (>40 µM at 30 min).
Compounds 25b-d and 49a-b were tested in the marmoset facial
blood flow assay as previously described.23 The results for 25b-c and
49b were shown in Fig. 2. Briefly, marmosets were anesthetized, and
facial blood flow was increased by intravenous (iv) administration of
h
α
CGRP (10 µg/kg) at 45 min intervals (ꢀ 30, 15, 60, 105 min) (Fig. 2).
The effect of different doses of antagonists, delivered subcutaneously
Pharmacokinetic studies also assessed oral exposures in vivo. With a
10 mg/kg oral dose, compound 25b exhibited only 1% bioavailability in
the rat with Cmax of 29 nM (less than the 4 h coarse PK Cmax of 96 nM).
(sc) at 0 min, on the hαCGRP-induced increases in facial blood flow was
measured by laser Doppler flowmetry. In this assay, compounds 25b-c,
and 49 showed exposure-dependent inhibition of CGRP-induced
5

G. Luo et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128077
4 Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new
migraine therapies - successful translation from bench to clinic. Nature Rev Neurol.
2018;14:338–350.
Table 2
Selected data for 25b, 25c and 49b.
5 (a) Edvinsson L. New therapeutic target in primary headaches – blocking the CGRP
receptor. Expert Opin Ther Targets. 2003;7:377–383.(b) Durham PL. CGRP-receptor
antagonists — A fresh approach to migraine therapy? N Engl J Med. 2004;350:
1073–1075.
Compound
25b
25c
25f
49b
MW
633
701
674
627
H-bond D/Aa
2/8
2/8
2/9
2/8
cLogPb
3.31
3.60
3.09
118
3.03
114
6 (a) Conway CM, Dubowchik GM, Coric V. Rimegepant and BHV-3500, small
molecule CGRP receptor antagonists, exhibit no active vasoconstrictive properties in
ex vivo human coronary or cerebral arteries. Headache. 2018;58:1295.(b) Rubio-
Beltran E, Chan KY, Danser AJ, MaassenVanDenBrink A, Edvinsson L.
Characterisation of the calcitonin gene-related peptide receptor antagonists
ubrogepant and atogepant in human isolated coronary, cerebral and middle
meningeal arteries. Cephalalgia. 2020;40:357–366.
tPSAb
105
105
PAMPA (nm/s) pH5.5/7.4
Caco-2 Pc A-B/B-A (nm/sec)
Solubilityc (µg/ml)
NT/192
<15/196
<1
513/NT
<15/24
<1
28/23
<15/165
<1
99/87
<15/257
15
a
Numbers of hydrogen bond donor and acceptor.
Calculated by Chemdraw 16.
b
c
7 (a) Oleson J, Diener HC, Husstedt IW, et al. Calcitonin gene-related peptide receptor
antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 2004;
350:1104-1110; (b) Rudolf K, Eberlein W, Engel W, et al. Development of human
calcitonin gene-related peptide (CGRP) receptor antagonists. 1. Potent and selective
small molecule CGRP antagonists. 1-[N2-[3,5-Dibromo-N-[[4-(3,4-dihydro-2(1H)-
oxoquinazolin-3-yl)-1-piperidinyl]carbonyl]-d-tyrosyl]-l-lysyl]-4-(4-pyridinyl)piper-
azine: The first CGRP antagonist for clinical trials in acute migraine. J Med Chem
2005;48:5921-5931.
Measured in 50 mM phosphate buffer (pH 7) as an amorphous solid. NT =
Not tested.
Compound 25b was dosed in the cynomolgus monkey (cyno) at 10 mg/
kg and revealed a Cmax of 35 nM, while the Cmax of 25c and 25d were
87 and 230 nM, respectively, when dosed in cynomologous monkeys at
10 mg/kg. Poor oral bioavailability is likely due to overall poor physi-
cochemical properties of these rigid molecules with high molecular
weight (MW), which appeared to be P-glycoprotein (P-gp) substrates
(Table 2). Furthermore pharmaceutics challenges remained (i.e., very
poor aqueous solubility, Table 2) and it seemed to be unlikely that all of
the required molecular features for good oral bioavailability could be
incorporated into one molecule in this series of CGRP antagonists,
despite our extensive SAR studies around the azepinone core.
8 (a) Paone DV, Shaw AW, Nguyen DN, et al. Potent, orally bioavailable calcitonin
gene-related peptide receptor antagonists for the treatment of migraine: discovery of
N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4- (2-
oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (MK-
0974). J Med Chem. 2007;50:5564–5567.(b) Nguyen DN, Paone DV, Shaw AW, et al.
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In summary, we have modified a novel CGRP receptor antagonist
azepinone series by replacing the fused indazole portion with various
heterocycles. In general, these compounds showed excellent binding
affinities against the human CGRP receptor. Five compounds tested in
the marmoset facial blood flow assay showed very good efficacy.
However, oral bioavailability remained low, emphasizing the challenges
we and others have encountered in discovering development candidates
for this difficult Class B GPCR target. However, during the same time of
these efforts, our team was successful in a different series of CGRP re-
ceptor antagonists, leading to rimegepant (BMS-927711)24 that was
approved as Nurtec™ ODT.10
12 (a) Goadsby PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of orally
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13 Mercer SE, Chaturvedula PV, Conway CM, et al. Azepino-indazoles as calcitonin
gene-related peptide (CGRP) receptor antagonists. Bioorg Med Chem Lett 2021;32:in
press.
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Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
19 Mehta G, Dhar DN, Suri SC. Reaction of indoles with chlorosulphonyl isocyanate; a
versatile route to 3-substituted indoles. Synthesis. 1978:374–376.
Appendix A. Supplementary data
20 Sassatelli M, Bouchikhi F, Messaoudi S, et al. Synthesis and antiproliferative
activities of diversely substituted glycosyl-isoindigo derivatives. Eur J Med Chem.
2006;41:88–100.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128077.
21 Compound 41 could be easily converted to the indanone as shown below but it was
also unstable under LiOH hydrolysis condition. No milder hydrolysis condition was
attempted with this intermediate.
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7