Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2020.127624

Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP K_i = 0.023 nM) that has

Full text of DOI:10.1016/j.bmcl.2020.127624

Journal Pre-proofs
Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor antag‐
onists
Stephen E. Mercer, Prasad V. Chaturvedula, Charles M. Conway, Deborah A.
Cook, Carl D. Davis, Sokhom S. Pin, Robert Macci, Richard Schartman,
Laura J. Signor, Kimberly A. Widmann, Valerie J. Whiterock, Ping Chen,
Cen Xu, John J. Herbst, Walter A. Kostich, George Thalody, John E. Macor,
Gene M. Dubowchik
PII:
S0960-894X(20)30735-6
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127624
BMCL 127624
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
8 July 2020
9 October 2020
14 October 2020
Please cite this article as: Mercer, S.E., Chaturvedula, P.V., Conway, C.M., Cook, D.A., Davis, C.D., Pin, S.S.,
Macci, R., Schartman, R., Signor, L.J., Widmann, K.A., Whiterock, V.J., Chen, P., Xu, C., Herbst, J.J., Kostich,
W.A., Thalody, G., Macor, J.E., Dubowchik, G.M., Azepino-indazoles as calcitonin gene-related peptide (CGRP)
receptor antagonists, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.
2020.127624
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Azepino-indazoles as calcitonin gene-related
peptide (CGRP) receptor antagonists
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Stephen E. Mercera* , Prasad V. Chaturvedulab, Charles M. Conwayc, Deborah A. Cookd, Carl D. Davise,
Sokhom S. Pinf, Robert Maccig, Richard Schartmanh, Laura J. Signor, Kimberly A. Widmann, Valerie J.
Whiterock, Ping Cheni, Cen Xue, John J. Herbst, Walter A. Kostichj, George Thalodyi, John E. Macork and
Gene M. Dubowchikc
H
Cl
N
H
N
N
N
N
O
F
O
N
N
F
F
N
N
N
N
O
O
H
O
O
NH
NH
N
21
zavegepant
(BHV-3500, BMS-742413)
hCGRP Ki = 0.023 nM
Rat FPO 1.7%
hCGRP Ki = 0.10 nM
Rat FPO 17%
H
Cl
N
H
N
N
N
N
O
F
F
F
O
N
N
N
N
N
N
O
O
H
O
O
NH
NH
N
21
zavegepant
hCGRP Ki = 0.10 nM
Rat FPO 17%
(BHV-3500, BMS-742413)
hCGRP Ki = 0.023 nM
Rat FPO 1.7%

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Azepino-indazoles as calcitonin gene-related peptide (CGRP) receptor
antagonists
Stephen E. Mercera* , Prasad V. Chaturvedulab, Charles M. Conwayc, Deborah A. Cookd, Carl D. Davise,
Sokhom S. Pinf, Robert Maccig, Richard Schartmanh, Laura J. Signor, Kimberly A. Widmann, Valerie J.
Whiterock, Ping Cheni, Cen Xue, John J. Herbst, Walter A. Kostichj, George Thalodyi, John E. Macork and
Gene M. Dubowchikc
Bristol-Myers Squibb, Wallingford, Connecticut 06492, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be
effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity
antagonist of the CGRP receptor (hCGRP Ki = 0.023 nM) that has demonstrated efficacy in the
acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral
bioavailability in rats (FPO = 1.7%). Using zavegepant as a template, we sought to improve oral
bioavailability through a series of azepinones which were designed in an attempt to reduce the
number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to
mostly maintain high affinity binding (hCGRP Ki = 0.100 nM) and in vivo efficacy in the
marmoset facial blood flow assay, while greatly improving oral bioavailability (rat FPO = 17%).
Keywords:
Calcitonin gene-related peptide
Migraine
Caprolactam
Indazole
2009 Elsevier Ltd. All rights reserved.
F
OH
H
Br
O
Br
N
F
O
H2N
H
N
O
N
F
N
N
F
F
N
N
N
N
O
H
O
N
O
O
H
N
NH
telcagepant
olcegepant
N
F
F
H2N
F
O
O
O
F
F
N
N
H
NH
O
N
O
N
O
N
N
N
NH
ubrogepant
rimegepant
N
Figure 1: CGRP receptor antagonist clinical candidates
Migraine is a complex neurological disorder characterized by
intense headache, often accompanied by nausea with a heightened
sensitivity to light, sound and odors, that can last for hours or even
several days.1 Many years of research largely based on the now
outmoded idea that dilation of intracranial blood vessels is the
underlying pathophysiology of migraine led to the discovery of
triptans (5-HT1B/1D agonists),2 which are active vasoconstrictors.
Being non-selective in this respect, triptans are contraindicated in
patients with cardiovascular disease or hypertension, and are
known to have a number of undesirable side effects.3
A number of studies have shown that calcitonin gene-related
peptide (CGRP) is involved in the pathogenesis of migraine.4
Plasma levels of the 37-amino acid peptide, which is widely
distributed in the nervous system, are elevated in persons suffering
migraine attacks and reduced upon successful treatment.5 CGRP
receptor antagonism has been an attractive approach for the

pharmacophore. Not knowing the preferred orientation of the
indazole, both compounds 1 and 2 were prepared. Compared to 1,
compound 2, having a less extended core conformation, showed
an order of magnitude improved affinity vs. 125I-hCGRP binding
in SK-N-MC cell membranes in our previously disclosed assay
(Figure 2).9
N
HN
O
N
N
H
N
O
O
N
H
NH
1
N
N
hCGRP Ki = 55 nM
Having determined the preferred regioisomer of the
unoptimized indazole, we next set out to explore additional SAR,
first focusing on the left side of the molecule (Table 1). We soon
learned that lipophilic groups (R1) were preferred over polar
functionality in this region with the 2,2-dimethylpropyl and 2,2,2-
trifluoroethyl probes providing the highest affinity. This was in
contrast to the unconstrained series that led to zavegepant, and
suggested a binding mode for R1 more like telcagepant than
olcegepant, as subsequently observed in structural studies of the
receptor complex ectodomain10. It was also clear that, as was seen
in the non-constrained series, having substitution in the 7-position
of the indazole gave us a further boost in affinity. Transforming
the linking urea NH, expected to be a liability for permeability, to
a methylene group also proved beneficial.
N
O
N
N
H
N
N
O
N
H
N
O
NH
zavegepant
hCGRP Ki = 0.023 nM
9 Rotational degrees of freedom
O
N
N
N
O
H
O
N
NH
2
hCGRP Ki = 6 nM
6 Rotational degrees of freedom
hCGRP-R Ki
(nM)
Compound
R1
R2
X
2
3
4
5
6
CH2Ph
Me
H
H
H
H
H
NH
NH
NH
NH
NH
12
370
22
CH2-4Py
CH2CH2-4Py
7.1
170
CH2CH2N(Me)2
CH2CH2-N-
morpholine
7
H
NH
50
8
9
4-Piperidine
i-Pr
H
H
H
NH
NH
NH
290
59
Table 1. SAR of compound 2 modifications
10
2-Methylpropyl
14
H
R2
N
N
2,2-
11
12
13
H
Cl
Cl
NH
NH
NH
4.9
1.0
1.5
Dimethylpropyl
O
N
CH2Ph
X
N
R1
O
O
2,2-
N
NH
Dimethylpropyl
2,2-
14
15
Cl
Cl
CH2
CH2
0.41
0.23
Dimethylpropyl
CH2CF3
treatment for migraine. Initial entries into phase II and III clinical
trials, such as olcegepant and telcagepant (Figure 1) provided
robust proof of concept for this treatment strategy, showing
efficacy comparable to the triptans without the cardiovascular
liabilities.6 Recently a number of treatments targeting the CGRP
pathway have been approved.7 These include four injectable
signal blocking monoclonal antibodies as well as two oral small
molecule CGRP receptor antagonists, UbrelvyTM (ubrogepant) and
NurtecTM ODT (rimegepant).7
Previously, our group reported the discovery of the CGRP
receptor antagonist BMS-742413,8 now referred to as zavegepant
(BHV-3500).7 Zavegepant shows good intranasal bioavailability
and has demonstrated efficacy in phase II/III clinical trials for the
acute treatment of migraine. However, zavegepant has very low
oral bioavailability in rats (FPO 1.7%). As an alternative, we were
interested in developing a CGRP receptor antagonist that
possessed properties conducive to oral delivery. Suspecting that
zavegepant possessed too many rotational degrees of freedom, we
attempted to constrain the central portion of the molecule into a
caprolactam, effectively locking the orientation of the indazole
ring system with respect to other components of the

From among the more active examples, compound 14 was
chosen to assess oral exposure. Unfortunately, when 14 was dosed
orally in rats at 10 mg/kg it exhibited poor bioavailability (FPO
1.8%). By retaining the amide core (X = CH2), we sought to
improve oral bioavailability by modulating the GPCR-privileged
quinazolinone right side of the molecule (Table 2). Addition of a
fluorine ortho to the aniline nitrogen (16) provided a modest boost
in exposure with retention of binding affinity. A similar effect was
achieved with naphthyridinones, 17 and 19. Combining the
fluorine with the naphthyridinone in compound 18 provided a
further boost in oral bioavailability for compound 18 when
compared to compound 17, but came with a greater than 10-fold
loss in binding affinity in each case. The same 10-fold loss of
binding affinity was seen when the fluorine was incorporated into
the naphtheridinone ring of compound 19 to give 20. With
diazepinone 21
NO2
NO2
c
HO
N
a, b
NH2
25
27
26
N
e
N
d
NH
O2N
NH
29
28
H2N
O
HN
O
N
NH
f
N
NH
N
30
31
Rat
hCGRP- FPO at
Scheme 1. Reagents and conditions: (a) methanesulfonyl chloride, TEA,
Compound R1 R2 R Ki 10
THF; (b) DBU, CH2Cl2, 98%; (c) neat, 120 oC, 21 h, 78%; (d) H2, PtO2,
(nM) mg/kg
Table 2. Efforts to improve oral bioavailability through modifications
EtOH, 99%; (e) CDI, CH3CN, 80%; (f) H2, Pd/C, 85%.
we were able
Figure 2. Constraint of zavegepant (BHV-3500, BMS-742413)
(%)
of the GPCR- privileged component
to
restore
O
H
N
NH
Cl
N
14
C(CH3)3
C(CH3)3
0.23
1.8
N
O
O
N
R2
N
N
NH
O
16
17
0.31
0.75
4.7
4.5
F
R1
binding affinity while improving oral bioavailability. As with the
naphthyridinones, ortho fluorination (22) severely degraded
binding affinity. Contracting the ring to benzimidazolone 23 also
caused a loss in binding affinity, which could be regained by
replacing the benzo ring in 23 with a pyrido ring in 24.
O
NH
C(CH3)3
O
O
O
O
Of all the compounds prepared, 21 showed the best oral
bioavailability while retaining a level of CGRP receptor binding
affinity that was comparable to the highly polar intranasal
compounds. Compound 21 fully antagonized CGRP-induced
receptor activation in SK-N-MC cells8 with an IC50 = 0.27 ± 0.15
nM (n = 4). In vitro liver microsomal stability was low (T1/2 = 3.6,
2.2, 2.4, and 3.1 minutes in human, rat, monkey and dog,
respectively), while human plasma protein binding was in the
moderate-to-high range (fu = 2.8%).
HN
O
NH2
O
O
18
HNC(CH3)3
6.305
12
NH
O
a, b
c
O
F
HO
HO
O
d
32
I
33
34
O
I
O
O
NOH
O
H1N9
CF3
3.4
NH2
0.54
HN
O
e
g
f
O
O
O
O
O
O
O
O
O
36
O
37
38
O
O
O
O
O
O
O
O
NH
O
20
NH2
CF3
6.0
N.D.
Compound 21 was chosen for study in our marmoset facial
blood flow assay, used to assess the in vivo pharmacodynamics of
CGRP receptor antagonists.9 Measuring CGRP induced changes
in facial blood flow was shown to be a surrogate for the
intracranial arterial dilation that occurs when CGRP is released
during a migraine attack. In this assay, facial blood flow in
anesthetized marmosets is measured using a laser Doppler
technique, where four administrations of hCGRP (10 g/kg) are
delivered intravenously (IV) at 45 minute intervals (-30, 15, 60 and
105 minutes relative to drug delivery), each causing increased
NFH
N
N
NH
Cl
Cl
Cl
i
j
h
HO
O O
O
O
O
O
N
41
O
O
40
39
NHO
O
0.10
O
O
O
O
O
21
CF3
17
O
O
H
N
NH
N
NH
Cl
N
F
F
N
Cl
NH2
43
Cl
F
m
l
OH
N
F
F
Cl
N
F
k
22
O
CF3
9.2 O
N.D.
N.D.
5.5
F
NH
44
O
O
N
F
42
O
F
O
F
O
N
O
O
45
O
O
H
H
Cl
Cl
N
N
N
150
125
100
75
1000
100
10
O
O
Post-Drug
Total
Free
n
NH
Baseline
N
O
O
23
CF3
N
3.3
F
F
N
F
F
F
F
OH
N
O
O
O
46
NH
N
21
50
1
25
NH
N
24
CF3
0.09
**
**
**
105
0
0.1
Scheme 2. Reagents and conditions: (a) urea hydrogen peroxide, iodine, THF; (b)
-30
15
60
N
Time (min) of 4 CGRP i.v. injections relative to Compound 21
(Boc)2O, TEA, THF; (c) Ac2O, NaOAc, THF, 40% for 3 steps; (d) Pd(OAc)2 (5
mole%), Bu4N+Cl-, TEA, DMF, 90%; (e) H2, (-)-1,2-Bis((2R,5R)-2,5-
diethylphospholano)benzene(cyclooctadiene)rhodium (I) tetrafluoroborate (2
mole%), CH2Cl2, 98%; (f) TFA, CH2Cl2, 98%; (g) NCS, DMF, 90%; (h) isoamyl
nitrite, potassium acetate, 5% acetic acid – toluene, 70%; (i) Mg(OMe)2, MeOH,
95%; (j) 2M thionyl chloride in CH2Cl2, 50%; (k) K2CO3, CH3CN; (l) toluene, acetic
acid, 120 oC, 46 h, 60% 2 steps; (m) LiOH, THF, H2O, 99%; (n) TBTU, 31, DIEA,
DMF, 60%.
Figure 3. Pharmacodynamic activity of compound 21 in the marmoset
facial blood flow assay when challenged with four CGRP IV injections.
**p ≤ 0.001 vs. baseline.
facial blood flow. The first delivery establishes a baseline control
response, and subsequent deliveries, which are designed to mimic

severe migraine, represent robust CGRP agonist challenges to the
receptor antagonist 21 dosed at 0 minutes. The ideal route of
administration in the marmoset assay is subcutaneous (SC)
delivery, since anesthesia delays gastric emptying, subsequently
altering the PK profile of oral administration. When given SC at
5 mg/kg, compound 21 produced statistically significant (p ≤
0.001) reductions in marmoset facial blood flow of 27%, 41% and
47% at 15, 60 and 105 minutes respectively, compared to baseline
(Figure 3).
Current Affiliations
a Bristol Myers Squibb, Cambridge, MA 02142, United States
b Spectrum Pharmaceuticals, Irvine, CA 92618, United States
c Biohaven Pharmaceuticals Inc., New Haven, CT 06510, United
States
d Medtronic, North Haven, CT 06473, United States
e Amgen, Inc. Thousand Oaks, CA 91320, United States
f Cerevel Therapeutics Cambridge, MA 02141, United States
g Thermo Fisher Scientific, Branford, CT 06405, United States
h
Compound 21 was synthesized in a convergent manner in
which the diazepinone (31) and constrained indazole (46) portions
of the molecule were prepared separately and then coupled in a
final step. The synthesis of the right side diazapinone is outlined
in Scheme 1 the key steps being elimination of the alcohol from
25 to form 2-vinylnitrobenzene (26), followed by condensation
with 4-amino-1-benzylpiperidine (27) to yield compound 28.
Reduction of the nitro group preceded formation of the urea 30.
Deprotection of the piperidine nitrogen produced intermediate 31
(Scheme 1).
Preformulation Solutions, LLC. North Ridgeville, OH 44039,
United States
i Bristol Myers Squibb, Lawrenceville, NJ 08543, United States
j
National Multiple Sclerosis Society, New York, NY 10017,
United States
k Sanofi, Waltham, MA 02451, United States
References and notes
1.
Lipton, R. B.; Diamond, S.; Reed, M.; Diamond, M. L.; Stewart, W. F.
Cephalalgia 1998, 8, 1.
The indazole azepinone portion of 21 was synthesized starting
from 3-amino-2-methylbenzyl alcohol 32, which was iodinated
using iodine monochloride to give 33, followed by protection of
the aniline amine and alcohol (Scheme 2). Coupling of 34 with
itaconic acid diethyl ester 35 was carried out under Heck-like
conditions.11 The olefin in 36 underwent rhodium(II) catalyzed
asymmetric hydrogenation to impart the desired stereochemistry
to 37.12 Aniline deprotection was followed by introduction of
chlorine on the aromatic ring, gave 39. To introduce the indazole
40 we devised a novel mild, one pot diazotization and cyclization
reaction using isoamyl nitrite and potassium acetate in a solvent
system consisting of 5% acetic acid in toluene. Deprotection of
the benzyl alcohol using magnesium methoxide in methanol also
resulted in transesterification to the dimethyl esters 41. The
unmasked alcohol was then converted to the chloride 42, which in
turn was displaced by 2,2,2-trifluoroamine 43 in the presence of
potassium carbonate in acetonitrile. A solution of the newly
formed secondary amine 44 in toluene was then heated at reflux in
the presence of acetic acid to form the azepinone ring system 45.
The resulting ester was saponified to generate the carboxylic acid
46, which was coupled with compound 31 under standard amide-
forming conditions to yield compound 21.
2.
3.
Silberstein, S. D. Lancet 2004, 363, 381.
Goadsby, P. J.; Lipton, R. B.; Ferrari, M. D. N. Engl. J. Med. 2002, 45,
476.
(a) Edvinsson, L. Headache 2018, 58 Suppl 1, 33. (b) Goadsby, P. J.;
Holland, P.R; Martins-Oliveira, M.; Hoffmann, J.; Schankin, C.;
Akerman, S. Physiol. Rev. 2017, 97(2), 553. (c) Ashina, M.; Hansen,
J.M.; Do, T.P.; Melo-Carrillo, A.; Burstein, R.; Moskowitz, M.A. The
Lancet Neurology 2019, 18(8), 795.
4.
5.
6.
a) Goadsby, P. J.; Edvinsson, L.; Ekman, R. Ann. Neurol. 1990, 28, 183.
(b) Goadsby, P. J.; Edvinsson, L. Ann. Neurol. 1993, 33, 48.
(a) Olesen, J.; Diener, H. C.; Husstedt, I. W.; Goadsby, P. J.; Hall, D.;
Meier, U; Pollentier, S.; Lesko, L. M. N. Engl. J. Med. 2004, 350, 1104.
(b) Hewitt, D. J.; Martin, V.; Lipton, R. B.; Brandes, J.; Ceesay, P.;
Gottwald, R.; Schaefer, E.; Lines, C.; Ho, T. W. Headache 2011, 51,
533. (c) Tfelt-Hansen, P. Headache, 2011, 51, 118. (d) Connor, K. M.;
Shapiro, R.E.; Diener, H.-C.; Lucas, S.; Kost, J.; Fan, X.; Fei, K.;
Assaid, C.; Lines, C.; Ho, T.W.; Neurology 2009, 73(12), 970-977.
(a) Tepper, S. J. Headache 2018, 58 Suppl 3, 238. (b) Lipton, R.B.;
Croop, R.; Stock, E. G.; Stock, D. A.; Morris, B. A.; Frost, M.; (c)
Dubowchik, G. M.; Conway, C. M.; Coric, V.; Goadsby, P. J.; N. Eng.
J. Med. 2019, 381, 142-149. (d) Dubowchik, G. M.; Conway, C. M.;
Xin, A. W.; J. Med. Chem. 2020, ASAP. (e) BHV-3500, formerly
"vazegepant", is now referred to as "zavegepant" (za ve’ je pant). The
World Health Organization (WHO) International Nonproprietary
Names (INN) Expert Committee revised the name to "zavegepant"
which was accepted by the United States Adopted Names (USAN)
Council for use in the U.S. and is pending formal adoption by the INN
for international use.
Chaturvedula, P. V.; Mercer, S. E.; Pin, S. S.; Thalody, G.; Xu, C.;
Conway, C. M.; Keavy, D.; Signor, L.; Cantor, G. H.; Mathias, N.;
Moench, P.; Denton, R.; Macci, R.; Schartman, R.; Whiterock, V.;
Davis, C.; Macor, J. E.; Dubowchik, G. M. Bioorg. Med. Chem. Lett.
2013, 23, 3157.
Degnan, A. P.; Chaturvedula, P. V.; Conway, C. M.; Cook, D.; Davis,
C. D.; Denton, R.; Han, X.; Macci, R.; Mathias, N. R.; Moench, P.; Pin,
S. S.; Ren, S. X.; Schartman, R.; Signor, L.; Thalody, G.; Widmann, K.
A.; Xu, C.; Macor, J. E.; Dubowchik, G. M. J. Med. Chem. 2008, 51,
4858.
7.
In conclusion, we developed a series of azepinone based CGRP
receptor antagonists that exhibited high affinity in vitro hCGRP
receptor binding with improved rat oral bioavailability, as
compared to our intranasal lead, zavegepant. A lead compound
from this series, compound 21, exhibited statistically significant
inhibitory activity at all three time points against a robust CGRP
agonist challenge designed to mimic severe migraine in a
marmoset facial blood flow assay when dosed at 5 mg/kg SC.
Although a comprehensive dose-response was not conducted to
identify the maximal pharmacodynamic (PD) effect of compound
21, these data are consistent with the PD profile of the clinical
assets rimegepant13 and zavegepant8 which likewise showed early
onset and durable effects across the same time points in the
marmoset assay. Encouraged by our ability to modify the highly
polar chemotype from which our intranasal compounds originated
into one in which significant oral bioavailability was possible, we
continued to optimize this series. Results of those efforts will be
disclosed in due course.
8.
9.
10. Ter Harr, E.; Koth, E. M.; Abdul-Manan, N.; Swenson, L.; Coll, J. T.;
Lippke, J. A.; Lepre, C. A.; Garcia-Guzman, M.; Moore, J. M. Structure
2010, 18(9), 1083.
11. (a) Heck, R. F.; Org. React. 1982, 27, 345. (b) Jeffery, T.J.; Chem.
Commun. 1984, 19, 1287. (c) Crisp, G. T.; Chem. Soc. Rev. 1998, 27,
427.
12. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125.
13. Luo, G.; Chen, L.; Conway, C. M.; Denton, R.; Keavy, D.; Signor, L.;
Kostich, W.; Lentz, K. A.; Santone, K. S.; Schartman, R.; Browning, M.;
Tong, G.; Houson, J. G.; Dubowchik, G. M.; Macor, J. E. J. Med. Chem.
2012, 55, 10644.
Acknowledgements
The authors would like to thank Ed Kozlowski and Xiaohua Huang
for their assistance with chiral separation and structure elucidation.
Author Information

Table 1. SAR of compound 2 modifications
N
Scheme 1. Reagents and conditions: (a) methanesulfonyl chloride, TEA,
HN
THF; (b) DBU, CH2Cl2, 98%; (c) neat, 120 oC, 21 h, 78%; (d) H2, PtO2,
EtOH, 99%; (e) CDI, CH3CN, 80%; (f) H2, Pd/C, 85%.
O
Figure 2. Constraint of zavegepant (BHV-3500,NBMS-742413)
hCGRP-R Ki
Compound
R1
R2
X
N
N
H
H
O
(nM)
R2
O
N
N
N
H
NH
1
N
N
hCGRP Ki = 55 nM
2
3
4
CH2Ph
H
H
H
NH
NH
NH
NH
12
370
22
N
O
O
N
N
Me
H
N
N
O
N
N
H
X
N
N
O
R1
O
NH
O
CH2-4Py
zavegepant
N
O
NH
hCGRP Ki = 0.023 nM
9 Rotational degree5s of freedom
6
CH2CH2-4Py
CH2CH2N(Me)2
NH
7.1
170
N
N
O
H
O
N
NH
NH
2
H
hCGRP Ki = 6 nM
6 Rotational degrees of freedom
CH2CH2-N-
morpholine
7
H
NH
50
8
9
4-Piperidine
i-Pr
H
H
H
NH
NH
NH
290
59
O
O
O
HN
O
NH2
O
HN
O
O
a, b
c
35
O
HO
HO
O
d
10
2-Methylpropyl
14
NO2
32 NO2
I
33
34
I
O
c
HO
N
a, b
2,2-
O
11
12
13
H
Cl
Cl
NH
NH
NH
4.9
1.0
1.5
NOH2
Dimethylpropyl
HN
O
NH2
HN
O
25
e
27
26
g
f
O
CH2Ph
O
O
N
e
O
O
N
O
O
36d
O
O
38
37
NH
O2N
NH
2,2-
O
O
O
O
O
O
O
O
O
Dimethylpropyl
29
28
N
NH
N
NH
H2N
NH2
Cl
Cl
2,2-
Cl
i
j
14
15
Cl
Cl
CH2
CH2
0.41
0.23
h
HO
O
Dimethylpropyl
O
O
HN
O
O
N
O
O
O
NH
f
41
O
N
NH
40
39
N
O
O
CH2CF3
O
O
O
O
O
O
O
30
H
31
N
NH
N
NH
Cl
N
F
F
N
Cl
NH2
43
Cl
F
F
m
l
F
H
N
Cl
F
k
F
O
F
O
O
OH
N
F
F
42
H
44
150
125
100
75
1000
100
10
O
Br
Br
N
O
F
O
O
N
Post-Drug
Total
Free
O
O
O
45
O
O
Baseline
H2N
H
H
Cl
Cl
H
N
N
N
O
N
N
F
N
N
F
N
N
N
N
n
O
H
F
O
Figure 1: CGRP receptor antagonist clinical candidates
N
O
O
H
O
O
O
N
F
F
50
NH
F
N
N
F
F
telcagepant
1
olcegepant
OH
N
F
O
25
O
O
N
F
46
NH
N
**
**
**
105
0
0.1
21
F
Scheme 2. Reagents and conditions: (a) urea hydrogen peroxide, iodine, THF; (b)
-30
15
60
Time (min) of 4 CGRP i.v. injections relative to Compound 21
(Boc)2O, TEA, THF; (c) Ac2O, NaOAc, THF, 40% for 3 steps; (d) Pd(OAc)2 (5
H2N
F
O
O
O
mole%), Bu4N+Cl-, TEA, DMF, 90%; (e) H2, (-)-1,2-Bis((2R,5R)-2,5-
F
F
N
N
NH
O
N
H
O
O diethylphospholano)benzene(cyclo
N
octadiene)rhodium (I) tetrafluoroborate (2
Figure 3. Pharmacodynamic activity of compound 21 in the marmoset
facial blood flow assay when challenged with four CGRP IV injections.
**p ≤ 0.001 vs. baseline.
N
N
N
NH
mole%), CH2Cl2, 98%; (f) TFA,riCmHeg2eCpla2n,t98%; (g) NCS, DMF, 90%; (h) isoamyl
ubrogepant
nitrite, potassium acetate, 5% acetic acid – toluNene, 70%; (i) Mg(OMe)2, MeOH,
95%; (j) 2M thionyl chloride in CH2Cl2, 50%; (k) K2CO3, CH3CN; (l) toluene, acetic
acid, 120 oC, 46 h, 60% 2 steps; (m) LiOH, THF, H2O, 99%; (n) TBTU, 31, DIEA,
DMF, 60%.

Table 2. Efforts to improve oral bioavailability through modifications
of the GPCR- privileged component
H
Cl
N
N
O
N
R2
N
O
R1
Rat
hCGRP- FPO at
Compound
R1
R2
R Ki
10
(nM)
mg/kg
(%)
O
N
NH
14
C(CH3)3
0.23
1.8
O
N
NH
16
17
18
19
20
C(CH3)3
C(CH3)3
C(CH3)3
CF3
0.31
0.75
6.0
4.7
4.5
F
O
NH
O
NH
12
F
O
NH
0.54
6.0
3.4
O
NH
CF3
N.D.
F
O
N
NH
21
CF3
0.10
17
O
N
NH
22
23
24
CF3
CF3
CF3
9.2
3.3
N.D.
N.D.
5.5
F
O
NH
N
O
NH
N
N
0.09