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)

Article abstract of DOI:10.1021/jm070668p

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)- phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).

Full text of DOI:10.1021/jm070668p

5564
J. Med. Chem. 2007, 50, 5564-5567
Chart 1. Effect of Privileged Structure on Serum Shift
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)
Daniel V. Paone,*,† Anthony W. Shaw,† Diem N. Nguyen,†
Christopher S. Burgey,† James Z. Deng,† Stefanie A. Kane,‡
Kenneth S. Koblan,‡ Christopher A. Salvatore,‡
Scott D. Mosser,‡ Victor K. Johnston,‡ Bradley K. Wong,
Cynthia M. Miller-Stein, James C. Hershey,#
Samuel L. Graham,† Joseph P. Vacca,† and
Theresa M. Williams†
Departments of Medicinal Chemistry, Pain Research, Drug
Metabolism, and Molecular Endocrinology, Merck Research
Laboratories, P.O. Box 4, West Point, PennsylVania 19486
ReceiVed June 8, 2007
without adverse cardiovascular effects.8 Supporting data come
from clinical trials of the CGRP receptor antagonist, olcegepant,
where after iv infusion similar efficacy to the triptans was
observed but with no cardiovascular side effects.9 Our program
targeted potent CGRP receptor antagonists with favorable
pharmacokinetic profiles that would result in the first oral drug
in this class.
Previously we reported the discovery of a novel series of
small-molecule, non-peptide CGRP receptor antagonists cen-
tered around an aminocaprolactam template.10 This work led
to 1, a (3R)-amino-(6S)-phenylcaprolactam urea-linked to a
GPCR privileged structure11 containing a piperidinylphenyl-
imidazolinone (Chart 1). This compound showed good potency
in the CGRP binding assay12 (Ki ) 2 nM), but oral bioavail-
ability in dogs was low (F ) 6%), though more reasonable levels
were attained in rats (F ) 27%). Further evaluation revealed
chemical instability associated with the privileged structure,
specifically air oxidation of the imidazolinone ring. In addition,
though 1 had good potency in a cell-based assay measuring
inhibition of CGRP-stimulated cAMP production (IC50 ) 4 nM),
this value shifted 28-fold (IC50 ) 114 nM) when run in the
presence of 50% human serum, suggesting a significant degree
of plasma protein binding.
Various alternatives to the phenylimidazolinone were explored
with the goals of lowering serum shifts and improving chemical
stabilities of the final compounds (Chart 1). Though many of
the new derivatives, such as triazolinone 2 and benzodiazepinone
3, were stable, most had equally high serum shift values to 1.
An exception was the azabenzimidazolone13 derivative 4,
possessing only a 9-fold serum shift. This compound had good
oral bioavailability in dogs (F ) 41%) and was chemically
stable, though potency in the presence of human serum was
modest (IC50 ) 339 nM).14 Having identified an improved
privileged structure, our attention turned to SAR of both the
C-6 aryl substituent and the N-1 amide side chain moiety to
derive more potency while maintaining good oral bioavailabili-
ties.
Abstract: Calcitonin gene-related peptide (CGRP) has been implicated
in the pathogenesis of migraine. Herein we describe optimization of
CGRP receptor antagonists based on an earlier lead structure containing
a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenyl-
imidazolinone with an azabenzimidazolone gave stable derivatives with
lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety
revealed the potency-enhancing effect of the 2,3-difluorophenyl group,
and trifluoroethylation of the N-1 amide position resulted in improved
oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-
0974).
Migraines are episodic headaches lasting 4-72 h and
characterized by severe pain, often accompanied by nausea and
heightened sensitivity to light and sound.1 It is estimated that
13% of the general population suffers from this disabling
condition. Generally perceived as the most effective symptom-
atic treatment of acute migraine are members of the triptan class
of compounds. However, the vasoconstrictive effect of these
5-HT1B/1D agonists renders these compounds contraindicated for
use in patients with cardiovascular disease, and this concern
poses limitations on their use.2
Calcitonin gene-related peptide (CGRP) is a 37 amino acid
neuropeptide found in the CNS and periphery,3 with physi-
ological functions that include nociception, neurogenic inflam-
mation, and vasodilation.4 The CGRP receptor is heterodimeric,
composed of the G-protein-coupled calcitonin-like receptor (CL
receptor) and the receptor activity modifying protein 1 (RAMP1).5
Activation of the CGRP receptor results in stimulation of cAMP
production.
CGRP has been implicated in the pathophysiology of
migraine,6 as elevated CGRP levels are present during a
migraine attack and iv infusion of CGRP can induce migraine-
like headache in migraineurs.7 Because CGRP receptor antago-
nists lack a direct vasoconstrictive mechanism, this class of
compounds could prove effective in the relief of migraine
* To whom correspondence should be addressed. Phone: 215-993-2269.
Fax: 215-652-7310. E-mail: daniel_paone@merck.com.
† Department of Medicinal Chemistry.
The original synthetic route toward 1 required installation of
the phenyl and amide side chain groups early in the sequence.15
Additionally, chiral chromatography was necessary to obtain
‡ Department of Pain Research.
Department of Drug Metabolism.
# Department of Molecular Endocrinology.
10.1021/jm070668p CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/11/2007

Letters
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23 5565
Scheme 1. Synthesis of Caprolactam Derivatives via Olefin
potency enhancements with only modest increases in molecular
weight and lipophilicity.
Metathesis Routea
Next, extensive variation of the amide substituent was
undertaken to improve PK and further increase potency. In an
attempt to maintain low serum shifts, we focused on compounds
with side chains containing polar groups. Several hydroxy and
alkoxy derivatives indeed showed decreases in serum shifts and
corresponding potency increases in the shift assay. Methoxyethyl
derivative 24 was highly potent (Ki ) 0.3 nM) with only a 1.5-
fold serum shift, but oral bioavailability was poor in rats and
dogs. This was due in part to metabolic cleavage of the methyl
ether in vivo (rat Cl ) 32 mL min-1 kg-1) giving hydroxyl
metabolite 25, which was 14-fold less active. Amino analogs
generally exhibited negligible serum shifts, as morpholine 28
was highly potent in the shift assay (IC50 ) 3 nM). However,
oral bioavailability was very low, as most of the amino side
chain derivatives suffered from facile N-dealkylation and
extremely high clearance values.
Heteroaryl amide substituents were utilized as a means of
more subtly introducing polarity. Though potent compounds
could be obtained, pyridinylmethyl analogs such as 29 showed
only moderate to low oral bioavailabilities. The major metabolite
was identified as the pyridine N-oxide, which when indepen-
dently prepared and tested was equipotent (shift IC50 ) 11 nM)
but was not orally bioavailable in rats or dogs. Similarly,
thioethers such as sulfide 30 underwent oxidative metabolism,
with low levels of both the corresponding sulfoxide 31 and
sulfone 32 detected in vivo. While these metabolites were
actually more potent than the parent sulfide (sulfone shift IC50
) 2 nM), oral bioavailability was negligible.
a Conditions: (a) 2,3-dibromopropene, Et3N, CH2Cl2; (b) Cbz-D-allyl-
Gly, EDC, CH2Cl2; (c) Grubbs second generation Ru cat., CH2Cl2, 40 °C;
(d) TFA, CH2Cl2; (e) R1B(OH)2, PdCl2(dppf), Na2CO3, DMF/H2O, 75 °C;
(f) H2, 10% Pd/C, Boc2O, EtOAc; (g) NaH, R2X, DMF, 0 °C f room
temp; (h) TFA, CH2Cl2; (i) 4-nitrophenyl chloroformate, Et3N, THF, 0 °C,
then azabenzimidazolone piperidine, room temp.
the desired pure enantiomer. Therefore, a new synthesis was
developed relying on olefin metathesis chemistry (Scheme 1)
that allowed for facile and independent variation at both the R1
and R2 positions of final targets 9. Alkylation of amine 5 with
2,3-dibromopropene and EDC coupling with Cbz-protected
D-allylglycine16 gave diene 6 in good yield. The key cyclization
was accomplished with the Grubbs second-generation ruthenium
catalyst.17 The unprecedented vinyl bromide ring-closing me-
tathesis18 (RCM) was low-yielding (15%)19 and required high
catalyst loading (20-30%), but after deprotection, sufficient
quantities of key intermediate 7 could be obtained in only four
steps.20 Suzuki couplings with various boronic acids proceeded
cleanly, and hydrogenation of the styrene products with in situ
Boc reprotection resulted in readily separable cis/trans mixtures.
The desired trans isomers underwent smooth amide alkylation
with various electrophiles, and deprotection followed by urea
coupling with the azabenzimidazolone piperidine provided the
final targets 9.
In general, amide side chains composed of small alkyl groups
provided compounds with the best pharmacokinetic profiles in
this series. Though serum shifts were more pronounced for these
analogs than their heteroatom counterparts, Caco-2 permeabili-
ties were high (Papp ) (22-35) × 10-6 cm/s) and potencies
were largely maintained. Methyl and ethyl analogs 34 and 35
had particularly good dog PK profiles, with low clearances (4-8
mL min-1 kg-1) and high oral bioavailabilities of 60% and 61%,
respectively. Fluoroalkyl derivatives were more potent by 2- to
3-fold,22 exemplified by trifluoroethyl derivative 38 with a shift
IC50 of 11 nM. This compound also displayed good levels of
oral bioavailability in rats (20%) and dogs (35%). In rats,
clearance was low (9.4 mL min-1 kg-1) with a moderate iv
half-life (1.6 h) and a short po Tmax (0.67 h). In dogs, clearance
Initial investigations at the aryl position were accomplished
by isolating and testing final compounds as 1:1 cis/trans
mixtures, devoid of amide substitution, to allow for increased
SAR efficiency (Table 1).21 In the effort to reduce serum shifts
and improve solubilities, hydroxyl and heteroaryl analogs such
as 11-13 were among the first explored, but these compounds
suffered large losses in potency compared to phenyl analog 10.
Derivatives containing alkyl-linked substituents such as iso-
propyl (17) and benzyl (18) were also less potent. Ultimately
many derivatives were prepared, including 2, 3, and 4-substituted
hydroxy, methoxy, methyl, pyridyl, chloro, and fluoro com-
pounds. All substitutions resulted in decreased potencies save
for the halogenated analogs, including the 2-fluorophenyl (19,
Ki ) 37 nM) and 3-fluorophenyl (20, Ki ) 93 nM) derivatives.
These analogs were next prepared as their single enantiomers,
21 and 22, and potency increased to 22 and 51 nM, respectively.
Combination of these elements gave the 2,3-difluorophenyl
analog 23, which resulted in a better than expected 20-fold
increase in affinity (Ki ) 3.6 nM) vs the parent phenyl
compound 10. Potency in the shift assay was also greatly
improved (IC50 ) 22 nM). Oral bioavailability in rats was low
(5%), but overall the 2,3-difluorophenyl group provided large
was moderate at 17 mL min-1 kg-1
.
To more clearly differentiate lead compounds 34, 35, and
38, they were chosen for evaluation in our in vivo pharmaco-
dynamic model (Table 2). This assay involves topical application
of capsaicin to the forearm of a rhesus monkey, causing CGRP
release and increased localized dermal blood flow.23 Upon iv
antagonist administration, inhibition of the capsaicin-induced
increase in dermal blood flow can be quantified by laser Doppler
imaging. Plasma levels are determined at different doses,
generating a dose-response curve from which effective concen-
trations are calculated. While all three analogs were shown to
be efficacious in this model, 38 (EC50 ) 120 nM, EC90 ) 1000
nM) was the most potent by >3.5-fold. This derivative also
had low clearance (7.0 mL min-1 kg-1) and a good iv half-life
(2.8 h) in rhesus monkeys. Additionally, 38 showed >10000-
fold selectivity in a panel of assays representing over 160
receptors, transporters, and enzymes and was selected as a
clinical candidate.
In conclusion, synthetic advancements over our previous
routes made possible the efficient optimization of lead capro-

5566 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 23
Letters
Table 1. Potencies and Oral Bioavailabilities of Caprolactam CGRP Receptor Antagonists
cAMP + 50%
human serum
IC50 (nM)
b
Ki
cAMP
shift
rat F e
(%)
dog F f
(%)
compd
stereoa
R1
R2
(nM)
IC50 c (nM)
(fold)d
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
S
S
phenyl
phenyl
4-hydroxyphenyl
2-pyridinyl
3-pyridinyl
3-thiophene
2-methoxyphenyl
4-methylphenyl
isopropyl
benzyl
2-fluorophenyl
cyclopropylmethyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-methoxyethyl
2-hydroxyethyl
2-trifluoromethoxyethyl
2-dimethylaminoethyl
2-morpholinylethyl
(2-pyridinyl)methyl
2-methylthioethyl
2-(methylsulfinyl)ethyl
2-(methylsulfonyl)ethyl
cyclopropylmethyl
methyl
11 ( 2.9
83
770
4400
9900
470
1700
1100
470
610
37 ( 7.0
93
22
51
3.6
0.3
4.2
0.19 ( 0.03
4.9
0.5
0.9
0.7
1.7
0.5
1.4
2.7 ( 0.4
2.4 ( 0.9
1.4
0.9
0.77 ( 0.07
38
520
1000
340
700
9
1.3
7
41
R,S
R,S
R,S
R,S
R,S
R,S
R,S
R,S
R,S
R,S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
750
1800
2.4
380
920
150
340
65
220
14
2
15
1
16
4
2
2
8
3
620
250
1.6
1.7
3-fluorophenyl
2-fluorophenyl
3-fluorophenyl
120
250
22
3
23
6
8
3
10
8
5
2
21
22
30
10
1.8
1.1
1.6
1.5
1.5
6
1
1
5
4
1
1
11
2.8
5
2
3
5
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
2,3-difluorophenyl
5
6
<1
3
2
2
12
1
30
6
7
1
12
2
8
6
5
8
12
30
17
25
20
17
60
61
14
11
35
ethyl
2-fluoroethyl
2,2-difluoroethyl
2,2,2-trifluoroethyl
5
15
11 ( 2.1
S
2.2 ( 0.3
a Stereochemistry at aryl position (C-6) of caprolactam ring. R,S refers to approximately 1:1 diastereomeric mixtures. b Values without SEM indicate less
than three determinations; the coefficient of variation of the binding and cell-based assays is <0.3. Inhibition of [125I]CGRP binding to recombinant human
CL-receptor/RAMP1 membranes. c Inhibition of CGRP-stimulated cAMP production in E10 cells. d Ratio of cAMP + 50% human serum IC50/cAMP IC50.
e 10 mg/kg dosed as a suspension in 1% aqueous methylcellulose. f 1 mg/kg dosed as a suspension in 1% aqueous methylcellulose.
Table 2. Activity in Rhesus Pharmacodynamic Assay
cAMP + 50%
Supporting Information Available: Representative experi-
mental procedures, 1H NMR, HRMS, and HPLC data for all target
compounds, and protocols for the CGRP binding, cAMP, and rhesus
pharmacodynamic assays. This material is available free of charge
via the Internet at http://pubs.acs.org.
human serum
rhesus PD
EC90 (nM)
rhesus Cl b
rhesus
compd
IC50 a (nM)
(mL min-1 kg-1
)
t1/2 b (h)
34
35
38
22
30
11 ( 2.1
4000
3600 ( 1700
1000 ( 480
7.1
8.7
7.0
1.9
2.3
2.8
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