Discovery of MK-3207: A highly potent, orally bioavailable CGRP receptor antagonist

Article abstract of DOI:10.1021/ml900016y

Incorporation of polar functionality into a series of highly potent calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort to improve pharmacokinetics. This strategy identified piperazinone analogues that possessed improved

Full text of DOI:10.1021/ml900016y

pubs.acs.org/acsmedchemlett
Discovery of MK-3207: A Highly Potent, Orally
Bioavailable CGRP Receptor Antagonist
Ian M. Bell,*,† Steven N. Gallicchio,† Michael R. Wood,† Amy G. Quigley,†
Craig A. Stump,† C. Blair Zartman,† John F. Fay,‡ Chi-Chung Li,§ Joseph J. Lynch,
Eric L. Moore,^ Scott D. Mosser,‡ Thomayant Prueksaritanont,# Christopher P. Regan,
Shane Roller,# Christopher A. Salvatore,^ Stefanie A. Kane,^ Joseph P. Vacca,† and
Harold G. Selnick†
Departments of †Medicinal Chemistry, ‡In Vitro Sciences, §Clinical PK/PD, Central Pharmacology, ^Pain/Migraine, and
#Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486
ABSTRACT Incorporation of polar functionality into a series of highly potent
calcitonin gene-related peptide (CGRP) receptor antagonists was explored in an effort
to improve pharmacokinetics. This strategy identified piperazinone analogues that
possessed improved solubility at acidic pH and increased oral bioavailability in
monkeys. Further optimization led to the discovery of the clinical candidate 2-[(8R)-
8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-20-oxo-1,10,20,3-tetra-
hydrospiro[indene-2,30-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) (4), the most
potent orally active CGRP receptor antagonist described to date.
KEYWORDS MK-3207, calcitonin gene-related peptide, receptor antagonist, phar-
macokinetics
igraine is a common, neurovascular disorder char-
acterized by attacks of severe headache that are
highly disabling.1 The gold standard for acute treat-
associated adverse effects. These and other clinical studies
highlight the potential of CGRP receptor antagonists as a new
class of antimigraine therapeutics.13
M
ment of migraine is the triptan class of 5-HT1B/1D receptor
agonists.2 While these agents are effective for the majority of
migraineurs, they are contraindicated in patients with car-
diovascular disease because of their vasoconstrictive
effects.3
The evolution of telcagepant from high-throughput
screening lead 2 (Chart 1) has been described.14 We have
also reported the identification of spiroindane-based CGRP
receptor antagonists from lead compound 2.15 More re-
cently, we described the discovery of novel antagonists
including the high affinity compound 5 (Table 1).16 Herein,
we report the preliminary structure-activity relationship
(SAR) studies on 5, which led to the discovery of the clinical
candidate MK-3207 (4).
Lactam 5 had high receptor affinity (Ki = 39 pM) and
subnanomolar potency in a cell-based functional assay
(cAMP IC50 = 0.16 nM). It maintained similar potency in
the same functional assay run in the presence of 50%
human serum (cAMP þ HS IC50=0.35 nM), indicating that
the activity of 5 would not be dramatically affected by
plasma protein binding in vivo. When the pharmacokinetic
profile of compound 5 was investigated, however, a key
liability was discovered. While 5 possessed modest oral
bioavailability in rats (F=12%) and dogs (F=44%), it had
no oral bioavailability in monkeys even when dosed in a
solubilizing 90% PEG400 vehicle (Table 2). This was a signi-
ficant problem because most small molecule CGRP receptor
Calcitonin gene-related peptide (CGRP) is a 37 amino acid
neuropeptide that is widely distributed in the central and
peripheral nervous system.4 The CGRP receptor is com-
posed of the calcitonin receptor-like receptor (CLR), a family
B G protein-coupled receptor (GPCR), in association with
receptor activity modifying protein 1 (RAMP1) and receptor
component protein.5 A number of lines of evidence impli-
cated CGRP in migraine pathophysiology, and this led to
interest in the potential utility of CGRP receptor antagonists
as novel therapeutics for migraine.6 Importantly, CGRP
receptor antagonists are not direct vasoconstrictors, so this
approach may offer an advantage over the use of triptans.7,8
Clinical evidence for the utility of CGRP receptor anta-
gonists for the acute treatment of migraine was initially
obtained with olcegepant (1, Chart 1).9 This highly potent
CGRP receptor antagonist (Ki=10 pM) is not orally bioavail-
able but has shown compelling efficacy in a phase II clinical
trial when administered via intravenous infusion.10 More
recently, orally dosed telcagepant11 (3, Chart 1) was shown
to be effective for acute treatment of migraine in a phase III
study.12 In this study, telcagepant 300 mg demonstrated
efficacy comparable to zolmitriptan 5 mg but with fewer
Received Date: December 14, 2009
Accepted Date: January 5, 2010
Published on Web Date: January 12, 2010
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Table 1. CGRP Receptor Antagonist Data
compd
R1
R2
X
Y
*
CGRP Kia,b (pM)
cAMP IC50a,c (nM)
cAMP þ HS IC50a,d (nM)
3
5
770 (70 (13)
39 (12 (13)
120 (2)
2.2 ( 0.3 (8)
0.16 ( 0.06 (5)
0.59 (2)
11 ( 2 (10)
0.35 ( 0.10 (5)
1.4 (2)
Me
Me
Me
Et
Me
Me
Me
Et
CH2
CH2
O
F
H
H
H
F
F
F
F
F
F
S
6
S
7
R
R
R
R
R
R
R
S
82 ( 30 (5)
67 (18 (6)
18 ( 6 (3)
0.22 (2)
0.27 (2)
8
O
0.23 ( 0.04 (3)
0.32 ( 0.08 (3)
0.17 (0.03 (7)
0.14 (2)
0.37 (0.05 (3)
0.44 ( 0.12 (3)
0.25 ( 0.07 (7)
0.18 (2)
9
Et
Et
O
10
11
4
Me
Et
Me
Et
NH
NH
NH
NH
NH
34 (11 (27)
20 ( 4 (4)
-CH2CH2CH2CH2-
21 ( 6 (15)
17 ( 5 (7)
0.12 ( 0.05 (6)
0.22 ( 0.05 (3)
10 (2)
0.17 ( 0.07 (6)
0.33 ( 0.12 (3)
11 (2)
12
13
-CH2CH2CH2CH2CH2-
-CH2CH2CH2CH2CH2-
570 (110 (5)
a Mean value ( standard deviation, where appropriate; the number of replicates is in parentheses. b The Ki value for inhibition of 125I-hCGRP binding
was determined using membranes from HEK293 cells stably expressing human CLR/RAMP1.17 c Inhibition of CGRP-induced cAMP production in
HEK293 cells stably expressing human CLR/RAMP1.17 d Assay conditions are as for footnote c but were determined in the presence of 50% human
serum.17
antagonists exhibited species-selective pharmacology. Telca-
gepant, forexample, exhibited approximately1500-fold high-
er affinity for the human and rhesus CGRP receptors as
compared to the rat and dog receptors.17 Thus, oral bioavail-
ability in monkeys was an important requirement for the
comprehensive evaluation of the in vivo pharmacology of a
compound.
It was known that for telcagepant, intestinal first-pass
metabolism played a significant role in the low oral bioavail-
ability in monkeys.18 We suspected that a similar intestinal
first-pass effect was also contributing to the lack of rhesus
bioavailability for lactam 5. In vitro metabolism studies
indicated that 5 was subject to extensive oxidative meta-
bolism on the δ-valerolactam and its substituents. To reduce
the extent of such metabolism and also with the goal of
improving aqueous solubility, we sought to incorporate polar
functionality into this region of the molecule.
One strategy was insertion of a heteroatom in the lactam
ring to afford, for example, a morpholinone analogue.
The first such example was compound 7 (Table 1), which
maintained similar receptor affinity (Ki = 82 pM) to the
corresponding lactam 6 (Ki=120 pM). The 3,3-diethylmor-
pholinone analogue 8 performed similarly to its dimethyl
progenitor 7 in both the binding assay and the cAMP
functional assay (Table 1) but exhibited superior rat pharma-
cokinetics (Table 2).
Table 2. Pharmacokinetic Data
compd
species
Fa (%)
Clb (mL/min/kg)
5
rat
12
44
0c
7.4
17
16
dog
monkey
7
8
9
rat
rat
9
23
5
33
Chart 1. Selected CGRP Receptor Antagonists
rat
59
72c
0c
10
3.5
20
dog
monkey
10
rat
9
48
4.6
15
dog
16c
7
monkey
11
4
rat
28
8.2
rat
74
67d
9
11
8.0
15
dog
monkey
12
13
rat
61
38
1.8
6.2
dog
rat
44
41
a Determined after dosing in 1% methocel at 10 (rat), 1 (dog), or
2 mpk (monkey) except as noted. b Determined after dosing in DMSO at
2 (rat) or 0.5 mpk (dog and monkey). c Dosed in 90% PEG400. d Dosed
at 2 mpk.
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Table 3. Plasma Protein Binding Dataa
fu (%)
species led to a significant focus on such piperazinone
analogues.
The plasma clearance of 10 was low in dogs, moderate in
monkeys, and high in rats (Table 2). The plasma unbound
fraction of the compound was relatively high in all species,
ranging from 18.1% in rats to 42.9% in monkeys (Table 3).
Because replacement of the gem-dimethyl substituents in
morpholinone 7 with gem-diethyl groups led to reduced
clearance and improved F in rats for compound 8, a similar
strategy was explored for piperazinone 10.
compd
human
rat
dog
monkey
9
1.7
41.1
9.4
2.8
5.4
0.1
18.1
0.8
0.2
3.4
0.3
38.3
6.1
1.1
2.5
2.2
42.9
9.6
6.1
7.4
10
4
12
13
The 3,3-diethylpiperazinone 11 had slightly higher affinity
for the CGRP receptor as compared with 10 (Table 1), and as
anticipated, this modification afforded lower clearance (Cl=
8.2 mL/min/kg) and higher oral bioavailability (F=28%) in
rats. In analogy with the gem-diethyl analogues like 11,
constrained versions containing spirocycloalkyl moieties
were also synthesized. Both the spirocyclopentyl analogue
4 and the spirocyclohexyl version 12 were found to be potent
CGRP receptor antagonists in vitro (Table 1). Importantly, as
compared with the 3,3-dimethylpiperazinone 10, both 4
and 12 exhibited improved oral bioavailability in rats and
dogs (Table 2).
In rats, plasma protein binding was apparently a signi-
ficant factor in attenuating the clearance of these piperazi-
none analogues. As the size of the 3-position substituents
increased, rat free fraction and plasma clearance decreased
as follows: compound 10 ( fu=18.1%; Cl=48 mL/min/kg);
compound 4 ( fu=0.8%; Cl=11 mL/min/kg); and compound
12 ( fu=0.2%; Cl=1.8 mL/min/kg). Further evidence for the
key role of plasma protein binding was provided by com-
pound 13, the epimer of 12. Inversion of the piperazinone
stereocenter in 12 led to a significant (>30-fold) loss in affinity
for the CGRP receptor (Ta bl e 1 ). Interestingly, the rat free
fraction and clearance also increased significantly for 13 ( fu=
3.4%; Cl=41 mL/min/kg) as compared with 12. The fact that
epimers 12 and 13 exhibit 17-fold different rat free fractions
strongly suggests that the high level of plasma protein binding
observed for compound 12 in rats is due, at least in part, to
molecular recognition. There is apparently a protein in rat
plasma that binds 12 with much higher affinity than 13, and
thisinteraction has animportant influenceonthefreefraction
and, consequently, plasma clearance.
In contrast to the observations in rats, the clearance of
these piperazinone compounds did not seem to be highly
influenced by plasma protein binding in dogs and monkeys,
as illustrated by compounds 10 and 4. In dogs, the free
fraction drops significantly from 38.3% for 10 to 6.1% for 4,
but the plasma clearance is actually higher for 4 (Table 2). In
monkeys, the unbound fraction in plasma differs by 5-fold
for the two compounds (Table 3), but they exhibit the same
clearance (Table 2). On the basis of its favorable profile in
terms of in vitro potency and pharmacokinetics, compound
4 was selected for more detailed evaluation. A summary
of its pharmacokinetics in preclinical species is shown
in Table 4.
a Determined using equilibrium dialysis methodology.
Compound 8 possessed lower plasma clearance (5 vs
23 mL/min/kg) and higher F (33 vs 9%). This was initially
surprising in the context of our strategy to improve oral
bioavailability by increasing polarity: Morpholinone 8 was
more lipophilic (cLogP =3.63) than 7 (cLogP =2.58) and
contained more potential sites for metabolism; yet, it pos-
sessed reduced plasma clearance in rats.
Morpholinone 9, the 3,5-difluorophenyl analogue of 8,
had similar cell-based activity to the other morpholinones in
Table 1 combined with good rat bioavailability (F = 59%,
Table 2). On the basis of these encouraging results, a more
detailed investigation of the pharmacokinetic profile of 9
was conducted. In dogs, 9 was found to have low clearance
(Cl=3.5 mL/min/kg) and excellent oral bioavailability (F=
72%). However, in monkeys, the compound was not orally
bioavailable (Table 2). In part, this discrepancy between the
behavior of 9 in monkeys and the other species could be
explained by moderate-high clearance in monkeys as
compared with low clearance in rats and dogs (Table 2).
Moreover, it appeared that plasma protein binding contrib-
uted to the observed differences in clearance: The unbound
fraction of 9 (Table 3) was significantly higher in monkeys
( fu=2.2%) than in rats ( fu=0.1%) or dogs ( fu=0.3%).
Nonetheless, it seemed likely that intestinal first-pass
metabolism also contributed to the lack of monkey oral
bioavailability. It was known that the first-pass effect ob-
served with telcagepant could be saturated at higher oral
doses. However, the extremely low aqueous solubility of 9 (at
pH 4, solubility <0.0001 mg/mL) would probably make it
difficult to achieve the concentrations needed to saturate the
intestinal first-pass effect. To improve aqueous solubility, the
morpholinone ether functionality was replaced with an
amino moiety to give a piperazinone ring. An early example
of such analogues was compound 10, which gratifyingly
exhibited improved aqueous solubility as compared with
morpholinone 9, especially at acidic pH (at pH 4, solubility=
1.95 mg/mL; at pH 7, solubility=0.13 mg/mL). Importantly,
the incorporation of this solubilizing amine functionality in
10 was compatible with affinity for the CGRP receptor (Ki=
34 pM) and with functional potency in the presence of serum
(cAMP þ HS IC50=0.25 nM).
The improvements in solubility observed with 10
translated into measurable, albeit low, monkey oral bio-
availability (F=7%). Similar results were obtained in rats
and dogs for compound 10 (Table 2), and this demonstra-
tion of modest oral bioavailability in three preclinical
In rats and dogs, 4 exhibited low plasma clearance and a
low volume of distribution, resulting in plasma half-lives
of about 1 h. Exposure following oral dosing in rats and
dogs was approximately dose-proportional with excellent
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Table 4. Preclinical Pharmacokinetics of Compound 4
Scheme 1. Synthesis of Compound 4a
PO dose
(mpk)
Fa
(%)
PO Cmax
(μM)
IV t1/2
(h)
Clb
(mL/min/kg) (L/kg)
Vdss
a
b
b
species
rat
10
50
74
87
14
52
0.6
1.0
1.5
11
0.3
0.6
1.7
dog
2
10
67
87
2.6
10
8.0
15
monkey
2
20
9
41
0.13
3.5
a Determined after dosing in 1% methocel. b Determined after
dosing in DMSO at 2 (rat) or 0.5 mpk (dog and monkey).
bioavailability. In rhesus monkeys, moderate clearance and
a higher volume of distribution were observed with com-
pound 4. It appeared that a saturable first-pass metabolism
contributed to low monkey oral bioavailability, and the oral
bioavailability increased at higher doses (F=9% at 2 mpk;
F=41% at 20 mpk).
a Conditions: (a) Methyl 1-aminocyclopentanecarboxylate hydro-
chloride, Na3PO4, DMF. (b) Glycine ethyl ester hydrochloride,
NaCNBH3, AcOH, MeOH, 50 ꢀC. (c) Boc2O, DIEA, CH3CN, 60 ꢀC. (d)
Chiralcel OD, hexane:i-PrOH:Et2NH (60:40:0.1), (R)-enantiomer is
second major peak. (e) LiOH, H2O, THF. (f) (R)-5-amino-1,3-
dihydrospiro[indene-2,30-pyrrolo[2,3-b]pyridin]-20-(10H)-one,21 HATU,
NMM, DMF. (g) HCl, EtOAc, 0 ꢀC.
Compound 4 had excellent in vitro potency in the radi-
oligand binding assay (Ki = 21 pM) and the cell-based
functional assay (cAMP IC50=0.12 nM). There was a small
shift in the functional assay in the presence of human serum
(cAMP þ HS IC50=0.17 nM), consistent with the significant
unbound fraction of 4 in human plasma (fu=9.4%). In this
serum-shifted functional assay, 4 was about 65-fold more
potent than telcagepant (cAMP þ HS IC50=11 nM, Table 2).
When tested in a diverse panel of more than 160 enzymes,
receptors, channels, and transporters, 4 was found to be
>50000-fold selective. In this test panel, 4 showed the
highest affinity for the calcitonin receptor (Ki=1.09 μM).
Gratifyingly, the high level of in vitro potency of 4 against
the CGRP receptor translated into a pharmacodynamic
model run in anesthetized rhesus monkeys: the capsaicin-
induced dermal vasodilation (CIDV) model.17 In this model,
the plasma concentration that inhibited 90% of the CIDV
Table 5. Ligand Efficiency and Physicochemical Parameters
compd Δg (kcal/mol) MW HBD HBA cLogPa PSAb (Å2)
1
2
3
4
0.27
0.18
0.31
0.35
869
522
566
557
8
4
2
3
5
5
4
4
1.67
3.43
2.74
2.17
181
147
103
113
a Determined using ALogP98. b PSAcalculated by method of Clark.24
The quest for orally acting drugs that target the CGRP
receptor is nontrivial. In part, this may be a reflection of the
difficulty of identifying orally bioavailable antagonists that
target family B GPCRs, such as CLR, for which the endogen-
ous ligands are large peptides.14 A consideration of the
physicochemical properties of clinical candidates 1, 3, and
4 highlights some of the progress made to date (Table 5).
From the perspective of Lipinski's rule-of-five guidelines
for orally active drugs,22 all three clinical compounds have
high MW (>500), although 3 and 4, which are both orally
bioavailable, satisfy the other RO5 criteria. Both 3 and 4 also
meet the oral drug guidelines of Veber et al.,23 specifically
rotatable bond count e10 and polar surface area (PSA) e
140 Å2. During the evolution of 4 from the original HTS lead
2, there was a focus on the improvement of potency without
a significant increase in MW and an effort to reduce PSA,
to increase the probability of good oral absorption.24
These goals are reflected in improvements in ligand effi-
ciency from 2 (Δg=0.18 kcal/mol) to 4 (Δg=0.35 kcal/mol)
and a reduced count of H-bond donors and acceptors,
correlating with reduced PSA. The overall result is that
4 possesses similar receptor affinity to 1 but is orally active.
In conclusion, a series of highly potent CGRP receptor
antagonists have been optimized. To improve the pharma-
cokinetic profile, polar functionality was incorporated, lead-
ing to piperazinone analogues that possessed improved
solubility at acidic pH and increased oral bioavailability
in monkeys. Further modification focused on balancing
response (EC90) was 7 nM. For telcagepant, the CIDV EC90
=
994 nM, indicating that 4 was approximately 100-fold more
potent than telcagepant as a CGRP receptor antagonist in
vivo. On the basis of its potency, selectivity, pharmacoki-
netics, and overall profile, compound 4 was selected as a
development candidate.
The methodology used to synthesize compounds 4-13
has been described.19 The synthesis of compound 4 is
outlined in Scheme 1. Methyl 1-aminocyclopentanecarboxy-
late was alkylated with 3,5-difluorophenacyl bromide (14) to
give amino ketone 15. Interestingly, 15 was somewhat
unstable and could undergo oxidative dimerization. This
decomposition was minimized by storing intermediate 15
as the mesylate salt. The key step involved reductive amina-
tion of ketone 15 with glycine ethyl ester and cyclization of
the resulting amine in situ to afford, after Boc protection,
piperazinone 16.20 Chiral high-performance liquid chroma-
tography (HPLC) resolution of 16 and saponification gave
the carboxylic acid 17, which was coupled to (R)-5-amino-
1,3-dihydrospiro[indene-2,30-pyrrolo[2,3-b]pyridin]-20-(10H)-
one19,21 under standard conditions to give, after deprotec-
tion, the desired compound 4. The other piperazinone
compounds were synthesized analogously.
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antagonist potency, plasma protein binding, and in vivo
clearance. These efforts led to the discovery of the clinical
candidate 4, the most potent orally bioavailable CGRP
receptor antagonist described to date. The detailed pharma-
cological and clinical evaluation of 4 will be reported
elsewhere.
the first CGRP antagonist for clinical trials in acute migraine.
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SUPPORTING INFORMATION AVAILABLE Representative
experimental procedures, NMR, MS, and HPLC data for all new test
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. Tel: 215-652-6455. Fax: 215-652-7310. E-mail:
ian_bell@merck.com.
ACKNOWLEDGMENT We thank the MS and NMR groups for
spectroscopic data; Joe Pawluczyk for synthesis of key intermedi-
ates; Ken Anderson and Mary Beth Young for pharmacokinetic
analysis; Jennifer Adelsberger, Michael Lyman, Kim Michel, Maria
Michener, and Tamara Pittman for animal dosing; Matt Zrada for
plasma protein binding and solubility determinations; Constantine
Kreatsoulas for molecular modeling; and Sam Graham for helpful
discussions.
(13) Tepper, S. J.; Stillman, M. J. Clinical and preclinical rationale
for CGRP-receptor antagonists in the treatment of migraine.
Headache 2008, 48, 1259–1268.
(14) Williams, T. M.; Burgey, C. S.; Salvatore, C. A. Calcitonin gene-
related peptide antagonists for the treatment of migraine.
Prog. Med. Chem. 2009, 47, 1–35.
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