Discovery of (R)-4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-(3-(7- methyl-1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl) piperidine-1-carboxamide (BMS-694153): A potent antagonist of the human calcitonin gene-related peptide receptor for migraine with rapid and efficient intranasal exposure

Article abstract of DOI:10.1021/jm800546t

Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chemistry leads suffered from modest potency, significant CYP3A4 inhibition, and poor aqueous solubility. Herein, we describe the optimization of these leads to give 4 (BMS-694153), a molecule with outstanding potency, a favorable predictive toxicology profile, and remarkable aqueous solubility. Compound 4 has good intranasal bioavailablity in rabbits and shows dose-dependent activity in validated in vivo and ex vivo migraine models.

Full text of DOI:10.1021/jm800546t

4858
J. Med. Chem. 2008, 51, 4858–4861
Letters
Discovery of (R)-4-(8-Fluoro-2-oxo-1,2-
dihydroquinazolin-3(4H)-yl)-N-(3-(7-methyl-
1H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-
yl)piperidin-1-yl)propan-2-yl)piperidine-1-
carboxamide (BMS-694153): A Potent
Antagonist of the Human Calcitonin Gene-
Related Peptide Receptor for Migraine with
Rapid and Efficient Intranasal Exposure
Figure 1. Compounds 1-4.
Table 1. Screening Data for Compounds 1-4
compound
1
2
3
4
hCGRP Ki (nM)
0.55
0.87
0.084
NA
0.26
>40
4.0
0.010
36
0.013
26
CYP3A4-BFCa IC50 (µM)
CYP3A4-BZRb IC50 (µM)
solubility (mg/mL)
Andrew P. Degnan,* Prasad V. Chaturvedula,*
Charles M. Conway, Deborah A. Cook, Carl D. Davis,
Rex Denton, Xiaojun Han, Robert Macci, Neil R. Mathias,
Paul Moench, Sokhom S. Pin, Shelly X. Ren,
Richard Schartman, Laura J. Signor, George Thalody,
Kimberly A. Widmann, Cen Xu, John E. Macor, and
Gene M. Dubowchik
6.0
6.7
NA
15c
>500d
a BFC)7-benzyloxy-4-trifluoromethylcoumarin.b BZR)7-Benzyloxyresorufin.
c Amorphous material (pH 5). d Crystalline (pH 6.8).
Although this compound effectively demonstrated the first
clinical proof-of-concept, its acceptance in the market may be
limited in its current injectible formulation. In this context, we
undertook a medicinal chemistry effort to identify a potent
CGRP antagonist that could be administered by a more
convenient route.7,8
Departments of Neuroscience Chemistry, Neuroscience Biology,
Metabolism and Phamacokinetics, Bioanalytical Research,
DiscoVery Toxicology, Pharmaceutics, and Pharmaceutics
DeVelopment, Bristol-Myers Squibb Research & DeVelopment,
5 Research Parkway, Wallingford, Connecticut 06492
Intranasal (IN) delivery would seem ideally suited for the
treatment of migraine. Nasal sprays can be expected to deliver
a faster onset of action over traditional oral formulations.9
Indeed, studies with marketed IN triptans show that plasma
concentrations rise more rapidly and offer faster pain relief than
their oral forms.10 Additionally, nausea sometimes limits the
usefulness of oral compounds in migraneurs.11 A nasal spray
offers the possibility of treating even those patients suffering
from migraine-related emesis. The decision to pursue an IN
formulation imposed a number of compound requirements. First,
the molecule must have very high receptor potency and a large
free fraction in plasma because of the need to deliver a low
dose to the nasal cavity.12 Also, the compound should have very
high aqueous solubility as the entire dose must be delivered in
a small volume of water (e100 µL/nostril).13 Herein we describe
the identification of the potent CGRP antagonist 4 (BMS-
694153) for IN delivery.
ReceiVed May 12, 2008
Abstract: Calcitonin gene-related peptide (CGRP) has been implicated
in the pathogenesis of migraine. Early chemistry leads suffered from
modest potency, significant CYP3A4 inhibition, and poor aqueous
solubility. Herein, we describe the optimization of these leads to give
4 (BMS-694153), a molecule with outstanding potency, a favorable
predictive toxicology profile, and remarkable aqueous solubility.
Compound 4 has good intranasal bioavailablity in rabbits and shows
dose-dependent activity in validated in vivo and ex vivo migraine
models.
Introduction
It has been hypothesized that migraine headache is associated
with the dilation of cranial blood vessels.1 The current standard
of care, the triptans, are 5-HT1B/1D agonists and are believed to
act, in part, by the active, nonselective vasoconstriction of
intracranial arteries.2 However, because triptans are nonselective
vasoconstrictors, they are associated with a number of unpleasant
cardiovascular side effects and are contraindicated in patients
with hypertension or ischemic heart disease.3 Calcitonin gene-
related peptide (CGRP), an extremely potent vasodilator, has
been implicated in the pathogenesis of migraine.4 Studies have
shown that plasma levels of CGRP, a 37 amino acid peptide,
are elevated during migraine attacks.5 In addition, it has recently
been demonstrated that intravenous administration of the potent
CGRP receptor antagonist BIBN4096BS is accompanied by the
alleviation of pain in migraneurs.6 Importantly, preliminary
reports indicate that efficacy was achieved in the absence of
the cardiovascular side effects associated with the use of triptans.
A careful survey of journal and patent literature,14 revealed
a number of structural motifs common to known CGRP anta-
gonists. As such, the synthesis of compound 1 was undertaken
which incorporated several of these elements (Figure 1).
Compound 1 was found to be a potent inhibitor of CGRP in
the primary binding assay (Table 1). Unfortunately, further
evaluation of 1 revealed it to be a potent inhibitor of cytochrome
P450 3A4 (CYP3A4). To better understand the role that the
benzthiophene side chain played in the inhibition of CYP3A4,
a number of analogues with varied amino acid side chains were
prepared and tested for their ability to inhibit CYP3A4. One
heterocycle that proved very promising in this regard was the
indazole of compound 2, which conferred excellent potency in
the CGRP binding assay while greatly reducing CYP3A4
inhibition. Further work in the indazole chemotype led to
compound 3, containing a 7-methylindazole. This substitution
resulted in a dramatic increase in receptor potency while
* To whom correspondence should be addressed. For A.P.D.: Phone,
203-677-5750; Fax, 203-677-7702; E-mail, andrew.degnan@bms.com.
For P.V.C.: Phone, 203-677-6699; Fax, 203-677-7702; E-mail, prasad.
chaturvedula@bms.com.
10.1021/jm800546t CCC: $40.75
2008 American Chemical Society
Published on Web 07/30/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16 4859
preserving acceptable CYP3A4 inhibition. The profile of 3 in a
series of in vitro assays designed to predict pharmacokinetic
properties indicated low clearance based on the stability of the
compound in liver microsomes (human, rat, and mouse). Of
the major human metabolizing enzymes, only CYP3A4 was
moderately inhibited by 3 (other major isoforms >30 µM).
Although 3 emerged as an attractive lead, it did not have
sufficient aqueous solubility (Table 1) to support IN dosing. A
survey of closely related analogues revealed that compound 4,
differing only in the inclusion of a fluorine at C-8 of the
quinazolinone, had dramatically improved solubility (>500 mg/
mL) while retaining the positive attributes of 3 (vide infra)
(Figure 1). It is possible that the fluorine serves to polarize the
NH bond of the adjacent urea, rendering it a more potent
hydrogen bond donor and thereby enhancing solvation by water.
The binding affinity of 4 for the human CGRP receptor was
determined by inhibition of 125I-CGRP binding in SK-N-MC
cell membranes. Compound 4 displayed concentration-depend-
ent competitive inhibition with a Ki ) 0.0128 ( 0.0005 nM (n
) 10). Functional receptor antagonism for 4 was determined
by measuring concentration-dependent inhibition of CGRP-
stimulated cAMP production in SK-N-MC cells. The compound
Figure 2. Reversal protocol in human intracranial arteries.
was shown to be a full, competitive antagonist with EC50
0.0345 ( 0.010 nM (n ) 4). A measured Kb of 0.0161 nM was
in agreement with the binding Ki.
)
The selectivity of 4 for the CGRP receptor over other closely
related receptors15 in the calcitonin receptor family was assessed
using radioligand binding assays. Compound 4 displayed greater
than 10000-fold selectivity for CGRP over adrenomedullin
receptors 1 and 2, calcitonin, and amylin receptors 1 and 3.
Species-dependent CGRP receptor binding affinity of 4 was
determined for two additional species. In the marmoset,
compound 4 displayed affinity similar to that to that of the
human receptor. No inhibition of CGRP binding to the rat
receptor was observed at concentrations up to 1000 nM. This
result is consistent with earlier reports that small molecule
hCGRP-receptor antagonists show species-specific differences
with relatively poor activity against nonprimate receptors.16 This
is thought to be due to differences in receptor activity-modifying
protein 1 (RAMP1), one of the component proteins of the CGRP
receptor (vide infra).
Figure 3. Effect of sumatriptan and compound 4 on ex vivo human
coronary arteries.
Figure 4. Marmoset facial blood flow.
showed 4 to be a potent antagonist of CGRP-induced dilation
(Kb ) 0.028 nM).
Ex Vivo and in Vivo Studies
To examine the ability of 4 to antagonize CGRP-induced
blood vessel dilation, the compound was tested in a number of
assays utilizing ex vivo human intracranial arteries. In these
studies, each vessel ring was mounted between two wire hooks
and attached to a force transducer that measured arterial tone.
To test the antidilatory effect of 4, vessels were first contracted
with 10 mM potassium chloride (KCl), then fully dilated with
1 nM hRCGRP, and finally dilation was reversed by the
cumulative addition of increasing concentrations of 4 in half-
log units. Data analysis was performed for each vessel individu-
ally, fitting the concentration-response data to a four-parameter
logistic function by nonlinear regression analysis to estimate
the EC50 values. This study showed that compound 4 potently
reverses CGRP-induced dilation (Figure 2, EC50 ) 0.06 nM).
In a second experiment with ex vivo human intracranial
arteries, the shift of the CGRP dose-response curve was
measured at various concentrations of 4 (Schild Analysis).15
Each wire-mounted artery ring was preincubated for 30 min
with a single concentration (0.1-30 nM) of antagonist 4, then
contracted with 10 mM K+, followed by increasing concentra-
tions of hRCGRP to achieve full relaxation. This assay again
Active vasoconstriction by 5-HT1B/1D agonists reflects a key
liability of the triptans, which constrict human coronary artery
and are contraindicated in patients with coronary artery disease.
To study the role of 4 in active vasoconstriction, basal artery
tension was measured upon cumulative addition of the antagonist
in ex vivo human coronary arteries. As a positive control,
serotonin (10 µM) was added to each tissue bath at the end of
a test session to provide a measure of maximal contractility in
each vessel. Compound 4 did not produce measurable contrac-
tion in ex vivo human arteries up to 10 µM (Figure 3). In
contrast, sumatriptan produced concentration-dependent vessel
contraction up to ca. 59% of maximum (EC50 ) 311 nM). The
absence of active constriction exhibited by 4 is a reflection of
the different mechanism of action for CGRP antagonists, which
is an antidilatory effect (returning dilated vessels to normal).
This suggests that this class of agents may be free from the
mechanism-based cardiovascular liabilities associated with
triptans. To summarize, our studies on ex vivo human intrac-
ranial arteries show that 4 was effective at (i) reversing and (ii)
inhibiting CGRP-induced dilation of human intracranial arteries
but does not by itself constrict human coronary arteries.

4860 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16
Scheme 1. Synthesis of 8-Fluoroquinazolinonea
Letters
cavity of rabbits when sprayed as a solution. Tmax occurred
within 10 min for all doses. The IN bioavailability at doses of
1.0 and 0.3 mg/kg was 59% and 55%, respectively. Maximal
plasma concentrations were 1200 and 360 nM, respectively. For
the iv leg (0.5 mg/kg), mean clearance (Cl) was 13 ( 5.7 mL/
min/kg, volume of distribution (Vss) was 2.7 ( 1.0 L/kg, and
T1/2 was 11 h. Compound 4 was systemically present for 24 h
(>10 nM) after IN administration, suggesting the potential for
rapid onset and sustained effect. IN bioavailability in rabbit was
comparable to that observed in rats dosed intratracheally (73%)
and subcutaneously (43% with 25 mM PBS vehicle; 81-157%
with PG:D5W vehicle). In the cynomolgus monkey, the SC
bioavailability was 76% using a PG:D5W vehicle.
a (a) (i) Boc2O/THF/∆ (100%); (ii) 2 equiv t-BuLi/THF, then DMF
(96%). (b) NaBH4/THF (77%). (c) (i) Pyr/(56%); (ii) Pd/H2/HOAc (100%).
Binding of 4 (10 µM) to serum proteins in vitro was low
over a range of species, including human (fu ) 35-77%).
Compound 4 inhibited recombinant CYP3A4 (IC50 ) 25 µM,
BFC; 7.8 µM, BZR), recombinant CYP2D6 (IC50 ) 25 µM,
AMMC assay), and CYP2D6-mediated metabolism of dex-
tromethorphan in human liver microsomes (IC50 ) 1.6 µM).
Inhibition of recombinant CYP1A2, CYP2C9, and CYP2C19
and also the CYP3A4-mediated metabolism of testosterone was
characterized by an IC50 of greater than 40 µM. Compound 4
at 30 µM produced ≈19% inhibition of hERG channel activity,
suggesting a low potential for QT related electrocardiographic
changes. The combined results from sodium patch-clamp and
Purkinje fiber action potential Vmax suggest that 4 has minimal
impact on the sodium channel. Compound 4 at 10 µM showed
no significant potential for off-target liabilities in a broad panel
of receptor and ion channel binding and enzyme activity assays.
Current animal models of migraine primarily use rats.17
However, because small molecule hCGRP-receptor antagonists
(including 4) show poor activity against rodent CGRP recep-
tors,16 higher species were required to examine in vivo efficacy
against this target. Marmosets are the only animal reported to
have human-like CGRP receptor pharmacology. This is thought
to be due to the presence of a specific amino acid residue
(Trp74) in the RAMP1 sequence that is responsible for the
phenotype of the human receptor. Although primate migraine
models have been developed, they are generally invasive,
terminal procedures.18,19 As such, a novel noninvasive marmoset
recovery model for in vivo efficacy assessment of CGRP-
receptor antagonists was developed that utilizes facial blood flow
as a surrogate for intracranial artery diameter. In brief, mar-
mosets were anesthetized and facial blood flow was increased
by intravenous (IV) administration of hRCGRP (10 µg/kg) at
45 min intervals (-30, 15, 60, and 105 min). The effect of
antagonist 4, delivered at 0 min, on the hRCGRP-induced
changes in facial blood flow was measured by laser Doppler
flowmetry. In this model (Figure 4), compound 4 (0.003-0.03
mg/kg) showed dose-dependent inhibition of CGRP-induced
increases in marmoset facial blood flow upon subcutaneous (SC)
dosing. Robust inhibition was observed at 0.03 mg/kg at 15,
60, and 105 min postdose. At the next lower dose, 0.01 mg/kg,
strong inhibition was seen at 60 and 105 min, but not 15 min.
No effect was seen at 0.003 mg/kg. CGRP-induced increases
in marmoset facial blood flow were similar across all time points
in vehicle-treated animals. Comparing efficacy vs exposure at
the 15 min test time, plasma levels of 4 above 10 nM were
associated with robust in vivo efficacy.
Chemistry
The synthesis of quinazolinone 9 began with the protection
of 2-fluoroaniline as its tert-butyl carbamate (Scheme 1). The
incorporation of the carbamate facilitated an ortho-lithiation by
tert-butyllithium to afford aldehyde 6 upon trapping with
dimethylformamide.20 Reductive amination with 4-amino-1-
benzylpiperidine completed the backbone of this fragment. Upon
heating, the secondary amine underwent an intramolecular
cyclization with the extrusion of tert-butanol to afford the cyclic
urea. Catalytic hydrogenation cleaved the benzyl protecting
group to afford 9, ready for coupling.
Fragment 9 and amino ester 1021 were efficiently united with
carbonyldiimidazole to install the urea in 78% yield. Saponifica-
tion of the methyl ester with lithium hydroxide gave a nearly
quantitative yield of the carboxylic acid. Finally, PyBOP
mediated coupling with the commercially available 4-piperidi-
nyl-piperidine completed the synthesis of 4 (Scheme 2).
In summary, we have discovered compound 4, a high-affinity
(Ki ) 0.0128 nM) CGRP receptor antagonist that incorporated
a novel 7-methylindazole amino acid as a key central subunit.
Introduction of a fluorine to the 3,4-dihydro-2(1H)-quinazoli-
Compound 4 did not exhibit significant oral bioavailability
in either the cynomolgus monkey or rat (Fpo e 0.3%),
presumably because of poor intrinsic permeability (Caco-2 Pc
< 15 nm/s). Because of the high aqueous solubility of 4 in the
pH range of 1-6.8 (>500 mg/mL), the IN route of administra-
tion was explored in rabbits.15 The IN pharmacokinetic profile
indicates that 4 is rapidly and efficiently absorbed from the nasal
Scheme 2. Synthesis of Compound 4a
a (f) CDI/THF, then 9 (78%). (g) (i) LiOH/THF/MeOH/H2O (96%); (ii) PyBOP/DIEA/DMF/DCM (63%).

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16 4861
boxamide (MK-0974). J. Med. Chem. 2007, 50, 5564–5567. (b)
Nguyen, D. N.; Paone, D. V.; Shaw, A. W.; Burgey, C. S.; Mosser,
S. D.; Johnston, V.; Salvatore, C. A.; Leonard, Y. M.; Miller-Stein,
C. M.; Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham, S. L.;
Williams, T. M. Calcitonin gene-related peptide (CGRP) receptor
antagonists: Investigations of a pyridinone template. Bioorg. Med.
Chem. Lett. 2008, 18, 755–758, and references therein.
(8) IDDB, Thomson Scientific reports that development of BIBN4096BS
has been discontinued.
(9) Behl, C. R.; Pimplaskar, H. K.; Sileno, A. P.; deMeireles, J.; Romeo,
V. D. Effects of physicochemical properties and other factors on
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none substituent led to dramatic increase in aqueous solubility
(>500 mg/mL, pH 1.0-6.8). The compound reverses CGRP-
induced dilation of ex vivo human intracranial arteries. At low
doses (0.03 mg/kg, SC), 4 shows robust inhibition of CGRP-
induced increases in marmoset facial blood flow, with rapid
onset of action (15 min) in vivo. Compound 4 exhibited a
favorable IN pharmacokinetic profile in rabbits with FIN ) 59%
( 22% and high plasma levels within 10 min, suggesting the
potential for rapid relief of migraine suffering.
Acknowledgment. We thank Joanne Bronson for help in
the preparation of this manuscript and the members of Discovery
Analytical Sciences for their help in the purification and
characterization of compounds contained herein.
(10) Rapoport, A. The Sumatriptan nasal spray: a review of clinical trials.
Cephalalgia 2001, 21, 13–15.
(11) Rapoport, A. M.; Bigal, M. E.; Tepper, S. J.; Sheftell, F. D. Intranasal
medications for the treatment of migraine and cluster headache. CNS
Drugs 2004, 18, 671–685.
(12) Wermeling, D. P; Miller, J. L.; Rudy, A. C. Systematic Intranasal
Drug Delivery: Concepts and Applications. Drug DeliVery Technol.
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(13) Merkus, P.; Guchelaar, H-.J.; Bosch, D. A.; Merkus, F. W. H. M.
Direct access of drugs to the human brain after intranasal drug
administration. Neurology 2003, 60, 1669–1671.
(14) Representative structural elements of 1 have been reported in: (a)
Rudolf, K. PCT Int. Appl. WO 98/11128 A1, 1998. (b) Hill, R. PCT
Int. Appl. WO 00/18764, 2000.
(15) See “Supplemental Biology Figures and Tables” section in Supporting
Information for graphic.
(16) Mallee, J. J.; Salvatore, C. A.; LeBourdelles, B.; Oliver, K. R.;
Longmore, J.; Koblan, K. S.; Kane, S. A. Receptor activity-modifying
protein 1 determines the species selectivity of non-peptide CGRP
receptor antagonists. J. Biol. Chem. 2002, 277, 14294–14298.
(17) (a) Escott, K. J.; Beattie, D. T.; Connor, H. E.; Brain, S. D. Trigeminal
ganglion stimulation increases facial skin blood flow in the rat: a major
role for calcitonin gene-related peptide. Brain Res. 1995, 669, 93–99.
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calcitonin gene-related peptide on dural vessel diameter in the
anaesthetized rat. Cephalalgia 1997, 17, 518–524. (c) Williamson,
D. J.; Hargreaves, R. J.; Hill, R. G.; Shepheard, S. L. Sumatriptan
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(18) Doods, H.; Hallermayer, G.; Wu, D.; Entzeroth, M.; Rudolf, K.; Engel,
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(19) More recently, a non-terminal procedure utilizing rhesus monkeys has
been developed. See ref 7b and references therein.
Supporting Information Available: Experimental details and
analytical data for the preparation of compounds 1-4, 6, and 8-11.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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JM800546T