Discovery of BMS-846372, a potent and orally active human CGRP receptor antagonist for the treatment of migraine

Article abstract of DOI:10.1021/ml300021s

Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification of potent and orally bioavailable compounds has been challenging. Herein, we describe the conceptualization, synthesis, and preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372). Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo efficacy in a marmoset migraine model.

Full text of DOI:10.1021/ml300021s

Letter
pubs.acs.org/acsmedchemlett
Discovery of BMS-846372, a Potent and Orally Active Human CGRP
Receptor Antagonist for the Treatment of Migraine
Guanglin Luo,* Ling Chen, Charles M. Conway, Rex Denton, Deborah Keavy, Michael Gulianello,
Yanling Huang, Walter Kostich, Kimberley A. Lentz, Stephen E. Mercer, Richard Schartman, Laura Signor,
Marc Browning, John E. Macor, and Gene M. Dubowchik
Molecular Sciences and Candidate Optimization, Neuroscience Biology, Bristol-Myers Squibb Research & Development,
5 Research Parkway, Wallingford, Connecticut 06492, United States
S
* Supporting Information
ABSTRACT: Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically
shown to be effective in the treatment of migraine, but identification of potent and orally bioavail-
able compounds has been challenging. Herein, we describe the conceptualization, synthesis, and
preclinical characterization of a potent, orally active CGRP receptor antagonist 5 (BMS-846372).
Compound 5 has good oral bioavailability in rat, dog, and cynomolgus monkeys and overall
attractive preclinical properties including strong (>50% inhibition) exposure-dependent in vivo
efficacy in a marmoset migraine model.
KEYWORDS: migraine, CGRP, CGRP receptor, antagonist
igraine is a chronic debilitating disease, affecting roughly
12% of the U.S. population, with women being at least
Chart 1. Selected CGRP Receptor Antagonists
M
2-fold more susceptible than men.1 One early hypothesis, put
forward by Wolff, was that migraine pathophysiology was asso-
ciated with the dilation of cranial blood vessels.2 More con-
temporary efforts have focused on neural processes and the
potential roles of peripheral3 and central sensitization4 in the
neurobiology of headache. The triptan class of 5-HT1B/1D ago-
nists is the current standard of care for treating migraines, and
they are believed to primarily act by vasoconstriction of cranial
vessels with concomitant inhibition of neurotransmitter release
from trigeminal afferents.5 However, triptans are associated
with a number of unpleasant side effects including chest and
neck tightening and are contraindicated in patients with cardio-
vascular disease and hypertension.6
The calcitonin gene-related peptide (CGRP), a 37 amino-
acid peptide, is widely distributed in the nervous system.7
CGRP is an extremely potent vasodilator that has been impli-
cated in the pathogenesis of migraine.8−10 Studies have shown
that plasma levels of CGRP are elevated during migraine
attacks.11,12 The CGRP receptor is composed of a family B G-
protein-coupled receptor (GPCR), named the calcitonin
receptor-like receptor (CLR), along with a receptor activity
modifying protein 1 (RAMP1).13 CGRP receptor antagonists
are attractive therapeutic targets for the treatment of migraine,
and several have demonstrated clinical efficacy. Intravenous ad-
ministration of the highly potent CGRP receptor antagonist
BIBN4096BS (1, Chart 1) was accompanied by alleviation of
pain in migraineurs without the cardiovascular side effects asso-
ciated with the use of triptans.14 While this compound
effectively demonstrated the first clinical proof of concept, its
route of administration and chemical instability precluded fur-
ther development.15 More recently, an oral CGRP receptor an-
tagonist, telcagepant (MK-0974)16 (2, Chart 1), was advanced
Received: January 23, 2012
Accepted: February 27, 2012
Published: February 27, 2012
© 2012 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
to phase III trials and demonstrated clinical efficacy but was
discontinued possibly due to toxicity issues.17,18
yield using triethylsilane and trifluoroacetic acid (TFA) in CH2Cl2.25
Dihydroxylation was effected under standard osmium-catalyzed
4-methyl morpholine N-oxide (NMO) conditions26 to give diol
10, followed by tri-tert-butyl-silyl (TBS) protection to afford
the monoprotected, inseparable diastereomeric mixture of 11 in
84% yield (two steps). Following Dess-Martin oxidation of the
alcohol intermediate 15, the two diastereomers of the ketone
intermediate 12 and 13 were separated. The structure of the
trans isomer 13 was identified by X-ray crystallography.27 Using
literature conditions,28 the formation of the pyridine derivative
14 from the ketone 13 with propargylamine under gold(III)
catalysis occurred in 20% yield. Treatment of 14 with tetra-
butylammonium fluoride (TBAF) afforded the racemic penul-
timate intermediate 15 in good yield. The alcohol 15 was
coupled with 1620 to provide racemic 5 in good yield. The final
desired product, 5 (BMS-846372), was separated by chiral pre-
parative high-pressure liquid chromatography (HPLC), from its
enantiomer 17.29 This 10-step synthesis was used to synthesize
the original lots of BMS-846372.
The primary issues with our original overall scheme were an
early high dilution RCM reaction, the low yields of pyridine
from the ketone 13, and the difficulty in controlling both dia-
stereomeric and enantiomeric selectivities. Thus, when gram
quantities of 5 were needed for more extensive preclinical eval-
uations, the route shown in Scheme 1 proved difficult to scale
up. Because formation of the pyridine ring (14) in Scheme 1
was a very low yielding step, a more focused approach using
commercially available pyridines became more attractive.
Accordingly, a second route was developed for the synthesis
of the penultimate 15, starting with commercially available 2-
bromo-3-pyridinecarboxaldehyde (Scheme 2). A simple Wittig
reaction led to the formation of 2-bromo-3-vinylpyridine 18 in
good yield.30 Lithium-halogen exchange of 18 followed by
addition of penten-4-al and TIPS-Cl afforded the desired diene
19 in 74% yield. While direct RCM with 19 gave no reaction,
treatment of the HCl salt31,32 of 19 under standard RCM con-
ditions with the (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidin-
ylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)-
ruthenium (Grubbs-II) catalyst gave the desired cycloheptene
20 in 86% yield. Racemic epoxidation of 20 with a racemic
Jacobson's catalyst33,34 afforded the epoxide 21 in 70% yield.
After hydrogenolysis of the epoxide 21, the resulting alcohol 22
was converted to the ketone 23 by Swern oxidation in good
yield. Triflate 24 was formed under standard conditions in 86%
yield, and Suzuki coupling with commercially available 2,3-
difluorophenylboronic acid also proceeded smoothly to afford
25. Deprotection with TBAF afforded the unsaturated alcohol
26 in 81% yield. Hydrogenation of 26 gave a mixture of the
desired alcohol 15 and its diastereomer 27. After separation
using flash column chromatography (FCC), 27 was converted
to 15 by a Mitsunobu reaction. Multigram quantities of 5 were
able to be prepared by this route, again through chiral HPLC
separation, which allowed for extensive preclinical evaluation of
5. Compound 5 was crystallized, and its relative stereo-
chemistry was proved by X-ray crystallography.29
A recent publication from our laboratories disclosed a potent,
indazole-based CGRP receptor antagonist (BMS-694153) (3,
Chart 1) that showed rapid and efficient intranasal exposure.19
However, BMS-694153 did not have significant oral bioavail-
ability in either a cynomolgus monkey or a rat primarily due to
its poor intrinsic cellular permeability. While intranasal delivery
is potentially attractive for migraine treatment, another one of
our goals was to discover novel, orally active CGRP antagonists.
In a recent publication, we disclosed that pyridine served as an
efficient mimetic of the secondary amide in BMS-694153,
providing antagonists with excellent binding potency and
improved bilayer permeability.20 Yet, despite this improvement,
significant oral exposure was still difficult to achieve in this
series. It proved difficult to incorporate optimal physiochemical
and pharmacokinetic properties in a single molecule. However,
one pyridine derivative (4, Chart 1) did demonstrate moderate
efficacy (31% inhibition) in the marmoset facial blood flow
model19 at 10 mg/kg when administered orally. To improve
oral exposure, we sought to reduce the number of rotatable
bonds and improve metabolic stability in our compounds by
constraining the pyridyl-containing core and further reducing
polarity by replacing the indazole moiety by a 2,3-difluorophenyl
ring. Herein, we describe the synthesis of BMS-846372 (5), a
potent CGRP receptor antagonist with good oral bioavailability
(Figure 1).
Figure 1. Structure of BMS-846372.
In compound 5, we incorporated an all-carbon 7-membered
ring fused to the pyridine to restrict its conformational flexi-
bility. A survey of the literature provided some simple cyclo-
heptapyridine structures, but there were no precedents for our
desired substitution pattern, particularly with the incorporation
of the two chiral centers. Even without a specific stereogenic
synthesis, the core bicyclic ring itself and the trans substitution
pattern posed some synthetic challenges. As a potentially
general route for exploration of pyridine substitution, our initial
attempts focused on the formation of a suitable 7-membered
ring on which the pyridine ring could be constructed. As such,
the first successful synthetic route to racemic 5 is outlined
in Scheme 1 with the formation of a key target intermediate
ketone 13. Thus, the dienyl ketone 6 was formed by reaction
of commercially available but-3-enylmagnesium bromide and
pent-4-enoyl chloride.21 The addition of 2,3-difluorophenyl
lithium generated from 1-bromo-2,3-difluorobenzene22,23 af-
forded alcohol 7 in a 55% yield. The formation of the 7-
membered ring 8 was achieved by ring-closure metathesis
(RCM) with benzylidene-bis(tricyclohexylphosphine)dichloro-
ruthenium (Grubbs-I) catalyst in 89% yield under high dilution
(0.012 M in CH2Cl2).24 Deoxygenation to 9 took place in 88%
Binding affinities for the human CGRP receptor were
determined by inhibition of 125I-CGRP binding in SK-N-MC
cell membranes as previously disclosed.19 Compound 5 dis-
placed 125I-CGRP with a Ki = 0.070 0.021 nM (n = 13), while
its enantiomer 17 had significantly reduced affinity with a Ki =
940 nM (Table 1). Functional receptor antagonism for 5 was
determined by measuring inhibition of CGRP-stimulated
cAMP production in SK-N-MC cells.19 The compound was
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ACS Medicinal Chemistry Letters
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a
Scheme 1. First Synthesis of 5 (BMS-846372)
a
Reagents and conditions: (a) THF, −78 °C to rt, 3 h (68%). (b) n-BuLi, THF, −78 °C to rt, 1 h (55%). (c) Grubbs-I, CH2Cl2 (0.012 M), 40 °C,
2 h (89%). (d) Triethylsilane, TFA, CH2Cl2, rt, 3 h (88%). (e) OsO4, NMO, acetone/water, 1 h. (f) TBS-Cl, DMF, rt, 5 h (84% for two steps). (g)
Dess-Martin periodinane, CH2Cl2, rt, 17 h (55% of 12 + 38% of 13). (h) Propargylamine, NaAuCl4·2H2O, EtOH, 80 °C, 5 h (20%). (i) TBAF,
THF, rt, 19 h (84%). (j) NaH, THF; rt, 18 h (46%), then chiral separation.
a
Scheme 2. Second Synthesis of BMS-846372 (5)
a
Reagents and conditions: (a) Methyltriphenylphosponium bromide, n-BuLi, THF, 72 h (89%). (b) n-BuLi, THF, 4-pentenylaldehyde, then TIPS-
Cl, −78 °C to rt (74%). (c) HCl; Grubbs-II, CH2Cl2, 40 °C, 4 h (86%). (d) ( )-[1,2-Cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)]-
manganese(III) chloride, NaOCl, Na2HPO4, CH2Cl2 (70%). (e) Pd/C/hydrogen (25 psi), EtOH, rt, 4 h (99%). (f) Oxalyl chloride, DMF
(cat.), −50 °C, CH2Cl2, Et3N (49%). (g) LDA, PhNTf2, THF, −78 °C to rt, 18 h (86%). (h) 2,3-Difluorophenylboronic acid, Na2CO3, Pd(PPh3)4,
toluene, 110 °C, 1.5 h (65%). (i) TBAF, THF, rt, 1 h (81%). (j) Pd/C/hydrogen (1 atm) (16% 15 and 74% 27). (k) 4-Nitrobenzoic acid, PPh3,
DIAD, THF, 0 °C to rt, 5 h; LiOH, rt, 3 h (77%).
Table 1. In Vitro Data for 5 and Its Enantiomer 17
shown to be an antagonist with an IC50 = 0.22
0.05 nM
(n = 2). BMS-846372 completely inhibited CGRP-mediated
elevation of cAMP.
A novel noninvasive marmoset recovery model for in vivo
efficacy assessment of CGRP-receptor antagonists was
developed in our laboratories, which utilized facial blood flow
compd
hCGRP Ki (nM)
5
17
0.070 ( 0.021)
940
cAMP IC50 (nM)
PAMPA (pH 5.5/pH 7.4) (nm/s)
0.22
1500/880
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ACS Medicinal Chemistry Letters
Letter
Figure 2. Marmoset facial blood flow.
as a surrogate for intracranial artery diameter, and the dilation
of arteries, which characterize a migraine.19 Briefly, marmosets
were anesthetized, and facial blood flow was increased
by intravenous (iv) administration of hαCGRP (10 μg/kg) at
45 min intervals (−30, 15, 60, and 105 min). The effect of
different doses of antagonist 5, delivered SC at 0 min, on the
hαCGRP-induced increases in facial blood flow was measured
by laser Doppler flowmetry. In this model, compound 5 showed
exposure-dependent inhibition of CGRP-induced increases in
marmoset facial blood flow upon subcutaneous (sc) dosing
(Figure 2).35 As compared to predose vehicle control (−30 min),
strong (>50%) inhibition of CGRP-induced effects on facial
blood flow was observed with 7 mg/kg of 5 at 60 and 105 min
postdose (52−60%) (Figure 2). In comparing exposure versus
efficacy with 7 mg/kg of 5 at the 60 and 105 min postdose test
times, plasma levels of 5 were above 1000 and 1500 nM,
respectively, and both times were associated with strong in vivo
efficacy (>50% inhibition).
With a 10 mg/kg dose po and 1 mg/kg iv, compound 5
exhibited significant oral bioavailability in the rat (Fpo = 29%),
dog (Fpo = 34%), and cynomolgus monkey (Fpo = 38%), cer-
tainly in part because of its high bilayer permeability (PAMPA:
880−1500 nm/s, Table 1). Compound 5 is reasonably stable
in human liver microsome with 74% remaining after 10 min
(0.5 μM) and with a t1/2 = 24 min. In addition, compound 5 at
10 μM showed no significant potential for off-target liabilities in
a panel of receptor, ion channel, and enzyme activity assays.
In conclusion, BMS-846372 is a potent CGRP antagonist,
with good oral bioavailability, strong exposure-dependent
in vivo efficacy, and acceptable off-target liabilities. It is active
in vivo and represents an opportunity for human dosing. Addi-
tional preclinical studies of BMS-846372 will be reported in due
course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and analytical data for the preparation of
compounds 6−15 and 17−27 and full characterization of BMS-
846372. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: 203-677-6640. Fax: 203-677-7702. E-mail: guanglin.luo@
bms.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Baoqin Ma for the X-ray analysis of the
intermediate 13 and 5 and the members of Discovery Analytical
Sciences for their help in the chiral separation and full
characterization of 5.
ABBREVIATIONS
■
CGRP, calcitonin gene-related peptide; GPCR, G-protein-
coupled receptor; CLR, calcitonin receptor-like receptor;
RAMP1, receptor activity modifying protein 1; THF, tetra-
hydrofuran; RCM, ring-closure metathesis; TFA, trifluoroacetic
acid; NMO, 4-methyl morpholine N-oxide; TBS, tri-tert-butyl-
silyl; TBAF, tetrabutylammonium fluoride; DIAD, diisopropyl
azodicarboxylate; HPLC, high-pressure liquid chromatography;
TIPS, tri-isopropyl-silyl; LCMS, liquid chromatography mass
spectrometry; Grubbs-I, benzylidene-bis(tricyclohexylphosphine)-
dichlororuthenium, bis(tricyclohexylphosphine)benzylidine
ruthenium(IV) dichloride; Grubbs-II, (1,3-bis(2,4,6-trimethyl-
phenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-
(tricyclohexylphosphine)ruthenium; FCC, flash column
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