Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-phenyl]-benzamide-based 5-HT1F receptor agonists: Evolution from bicyclic to monocyclic cores

Article abstract of DOI:10.1016/j.bmcl.2015.07.042

Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT_1F receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone moiety generated potent and more selective 5-HT_1F receptor agonists. Focused SAR studies around this central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with both the amide CONH group and the ketone C=O group play pivotal roles in affecting the adopted conformation and thus the 5-HT_1F receptor selectivity. Computational studies confirmed the observed results and provide a useful tool in the understanding of the conformational requirements for 5-HT_1F receptor agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also identified as potent and selective 5-HT_1F receptor agonists.

Full text of DOI:10.1016/j.bmcl.2015.07.042

Bioorganic & Medicinal Chemistry Letters 25 (2015) 4337–4341
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of selective N-[3-(1-methyl-piperidine-4-carbonyl)-
phenyl]-benzamide-based 5-HT1F receptor agonists: Evolution
from bicyclic to monocyclic cores
⇑
Deyi Zhang, Maria-Jesus Blanco , Bai-Ping Ying, Daniel Kohlman, Sidney X. Liang, Frantz Victor, Qi Chen,
Joseph Krushinski, Sandra A. Filla, Kevin J. Hudziak, Brian M. Mathes, Michael P. Cohen, DeAnna Zacherl,
David L. G. Nelson, David B. Wainscott, Suzanne E. Nutter, Wendy H. Gough, John M. Schaus,
Yao-Chang Xu
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Preclinical experiments and clinical observations suggest the potential effectiveness of selective 5-HT1F
receptor agonists in migraine. Identifying compounds with enhanced selectivity is crucial to assess its
therapeutic value. Replacement of the indole nucleus in 2 (LY334370) with a monocyclic phenyl ketone
moiety generated potent and more selective 5-HT1F receptor agonists. Focused SAR studies around this
central phenyl ring demonstrated that the electrostatic and steric interactions of the substituent with
both the amide CONH group and the ketone C@O group play pivotal roles in affecting the adopted con-
formation and thus the 5-HT1F receptor selectivity. Computational studies confirmed the observed results
and provide a useful tool in the understanding of the conformational requirements for 5-HT1F receptor
agonist activity and selectivity. Through this effort, the 2-F-phenyl and N-2-pyridyl series were also iden-
tified as potent and selective 5-HT1F receptor agonists.
Received 6 May 2015
Revised 15 July 2015
Accepted 17 July 2015
Available online 22 July 2015
Keywords:
Serotonin
Selectivity
5-HT1F
Conformation analysis
Electrostatic and steric interactions
Ó 2015 Elsevier Ltd. All rights reserved.
Serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter
widely distributed in the brain and peripheral tissue, produces its
receptor agonists do not contract the rabbit saphenous vein, an
effect that correlates well with contractile responses in the human
coronary artery.18,19 This indicates that the anti-migraine effect
may be achieved through 5-HT1F activation, and thus avoid
cardiovascular side-effects caused by 5-HT1B/1D activation.10
However, LY334370, like the ‘triptans’, possesses an indole core
structure, and also has appreciable 5-HT1A receptor affinity
(Ki = 22.1 nM), a possible cause for observed adverse effects such
as asthenia, dizziness and somnolence.
The goal of subsequent SAR studies was to improve 5-HT1F
receptor selectivity while maintaining high 5-HT1F receptor bind-
ing affinity and intrinsic efficacy. We chose to focus on identifying
5-HT1F receptor agonists without the indole nucleus which could
provide opportunities to improve selectivity over indole deriva-
tives and further differentiate from known triptans. We have pre-
effects through
Among these 5-HT receptors, the 5-HT1 class of receptors appears
to be the most complex and has been further classified into 5-HT1A
a
variety of membrane-bound receptors.1–3
,
5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F subtypes.4–6 The 5-HT1F recep-
tor was first identified and cloned in 1993.5,6 The mRNA for the
human receptor protein has been identified in the brain, mesentery
and uterus. Based on the localization of the 5-HT1F receptor, a
number of therapeutic indications have been proposed for both
agonists and antagonists at this receptor.7–11 One proposed indica-
tion for the 5-HT1F receptor agonists is the treatment of acute
migraine.
Sumatriptan (1) was the first 5-HT1 receptor agonist marketed
for the clinical treatment of migraine, and has high affinity for
5-HT1B, 5-HT1D and 5HT1F receptors (Fig. 1).7 LY334370 (2), a
potent and selective 5-HT1F receptor agonist,12–15 is also clinically
effective in ending migraine attacks.16,17 Unlike sumatriptan and
other 5-HT1B/1D receptor agonist ‘triptans’, selective 5-HT1F
viously
reported
that
pyrrolo[3,2-b]pyridine,20
furo[3,2-
b]pyridine,21 indazole and ‘inverted’ indazole, benzo[d]isoxazole22
systems can serve as replacements for the central indole ring and
provide potent and selective 5-HT1F receptor agonists.
In the synthesis of the previously reported indazole analogs,22
oxidative cleavage of the indole ring in LY334370 (2) followed by
hydrolysis provided compound 3 (Scheme 1). Interestingly, this
⇑
Corresponding author. Tel.: +1 (317) 433 3612.
E-mail address: blanco_maria@lilly.com (M.-J. Blanco).
http://dx.doi.org/10.1016/j.bmcl.2015.07.042
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

4338
D. Zhang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4337–4341
BBr3 yielded 12b. Compound 15 was synthesized in three steps from
N
N
4-bromo-1-fluoro-2-nitrobenzene (13) (Scheme 4): reduction of the
nitro group followed by acylation yielded compound 14. Treatment
of 14 with n-butyl lithium followed by Weinreb amide 5 provided
compound 15. For compound 18, analogous to the approach in
Scheme 3, 1-bromo-4-fluorobenzene (16) was converted to inter-
mediate 1723, which was further transformed into 18 through a
Buchwald-hydrolysis-acylation sequence.
F
H
N
H
N
S
O
O
N
H
O
N
H
1
2
Figure 1. Structures of sumatriptan (1) and LY 334370 (2).
The pyridyl analogs were synthesized according to Scheme 5.
The halo-pyridinyl-(1-methyl-piperidin-4-yl)-methanones 20a–b
and 23a–b were obtained from either halo-pyridines 19a–b or
halo-pyridine carboxylic acids 22a–b. Conversion of the halo
groups to the amino groups through Buchwald amination followed
by acylation afforded 21a–b and 24a–b.
compound showed nanomolar affinity at the 5-HT1F receptor
(Ki = 64 nM). This finding prompted us to study the effects of cen-
tral indole ring replacement with a mono-cyclic aromatic moiety
on 5-HT1F receptor binding affinity and selectivity.
The 4-fluoro-N-(3-(1-methyl-piperidine-4-carbonyl)-phenyl)-
benzamide (8) was synthesized from bromoaniline 4 (Scheme 2).
Protection of the amino group of 4 followed by lithium-bromo
exchange generated an anion which was reacted with Weinreb
amide 5 to provide intermediate 6. Hydrolysis of 6 followed by acy-
lation generated compound 8. Different synthetic approaches were
used to prepare the substituted phenyl analogs (Schemes 3 and 4).
The phenyl anions obtained through either mono-lithium-bromo
exchange (for 9a,c–e) of dibromo compounds, or selective deproto-
nation11 of 9f, were treated with Weinreb amide 5 to provide 10a,c–
f. Buchwald reactions followed by hydrolysis generated the corre-
sponding amines 11a,c–f. Treatment of amines 11a,c–f with 4-fluo-
robenzoyl chloride provided 12a, c–f. Demethylation of 12a with
The binding affinity of this series for the 5-HT1F, receptor as well
as selectivity ratio over 5-HT1A, 5-HT1B and 5-HT1D receptors is
reported in Table 1. The unsubstituted parent compound 8 showed
high affinity at the 5-HT1F receptor and increased selectivity at the
5-HT1A receptor than LY334370 (2). With this positive result, a
focused SAR was conducted to explore the substituent-based
effects on the preferred conformation of the new series so that it
would mimic the more rigid conformation of compound 2 to have
a strong binding affinity to the 5-HT1F receptor, yet be structurally
different enough to have improved receptor selectivity.
Considering the strong electronegativity of the fluorine atom, it
was hypothesized that its incorporation would change the electron
density distribution of the molecule, favoring certain conforma-
tions over others.24,25 Thus a fluorine walk around the central phe-
nyl ring was performed (12e,f, 15, 18) and the results indicated
that the 2-position of the phenyl ring would be an important posi-
tion to explore. Interestingly, substitution with other groups (12a–
d) at the 2-position all resulted in the loss of binding affinity at the
5-HT1F receptor.
N
N
F
F
a, b
H
N
H
N
O
O
O
Conformational analysis of these compounds indicates that
there are four distinctive low-energy conformations, cis–trans
(ct), cis–cis (cc), trans–trans (tt) and trans–cis (tc) (Fig. 2).26 The
ab initio calculations at B3LYP/6-31G⁄ level of theory using
Gaussian 9827 reveal that for compound 12f, the ct form is the
N
NH2
H
2
3
Scheme 1. Reagents and conditions: (a) NaIO4, MeOH, room temp, 51%; (b) 5 N
NaOH, MeOH, 45 °C, 51%.
F
O
O
O
H
H
N
a, b
c
d
H2N
Br
N
H2N
O
N
N
O
N
4
6
7
8
Scheme 2. (a) AcCl, Et3N, THF, room temp, 16 h, 75%; (b) MeLi, THF, À78 °C; then t-BuLi, 1-methyl-piperidine-4-carboxylic acid methoxy-methyl-amide (5), 81%; (c) 6 N HCl,
reflux, 1.75 h, 76%; (d) 4-fluorobenzoyl chloride, Et3N, THF, room temp, 98%.
R
Br
Br
R'
F
a
R
O
R
O
H
N
R
O
H2N
d
9a: R = OMe, R' = H
9c: R = Cl, R' = H
9d: R = Me, R' = H
9e: R = H, R' = F
Br
c
N
O
N
N
R'
R'
R'
11a, c-f
10a,c-e
10f: R = F, R'= H
12a: R = OMe, R' = H
12b: R = OH, R' = H
12c: R = Cl, R' = H
12d: R = Me, R' = H
12e: R = H, R' = F
12f: R = F, R' = H
b
e
F
Br
9f
Scheme 3. (a) n-BuLi, À78 °C, 5, 21–80%; (b) n-BuLi, 2,2,6,6-tetramethylpiperidine, 5, À78 °C, 35%; (c) (i) benzophenone imine, t-BuONa, Pd2(dba)3, BINAP, 80 °C, 8 h; (ii) 1 M
HCl, THF, 1 h; two-step: 37–80%; (d) 4-fluorobenzoyl chloride, dioxane, reflux, 3 h, 69–99%; (e) BBr3, CHCl3, 0 °C, 1.5 h, 60%.

D. Zhang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4337–4341
4339
F
F
O2N
F
Br
O
a, b
H
N
H
N
c
Br
O
O
N
F
F
13
14
15
O
F
O
F
Br
Br
H
d
e, b
N
N
F
F
O
N
16
17
18
Scheme 4. (a) SnCl2Á2H2O, EtOH, reflux, 1 h, 71%; (b) 4-fluorobenzoyl chloride, THF, rt, 1 h, 91% for 14, 100% for 18; (c) n-BuLi, 5, À78 °C, 42%; (d) TMEDA, n-BuLi, 5, À78 °C,
55%; (e) (i) benzophenone imine, t-BuONa, Pd2(dba)3, BINAP, 80 °C, 3.5 h, 63%; (ii) 1 M HCl, THF, 83%.
O
F
O
Cl
X
b, c
Cl
X
H
N
a
X
Y
Y
N
O
Y
N
20a-b
19a: X = N, Y = CH
19b: X = CH, Y = N
21a: X = N, Y = CH
21b: X = CH, Y = N
O
F
O
Z
CO2H
H
Z
b, c
d, e
N
Y
Y
X
N
X
O
Y
N
X
22a: X = N, Y = CH, Z = Br
22b: X = CH, Y = N, Z = Cl
24a: X = N, Y = CH
24b: X = CH, Y = N
23a-b
Scheme 5. (a) n-BuLi, 2-dimethylaminoethanol, 5, À78 to À40 °C, 38% for 20a, 33% for 20b; (b) (i) benzophenone imine, t-BuONa, Pd2(dba)3, BINAP, toluene, reflux, 2 h; (ii)
1 M HCl, THF; two-step: 40–47%; (c) 4-fluorobenzoyl chloride, Et3N, solvent, 34–90%; (d) O,N-dimethyl-hydroxylamine hydrochloride, EDCI, HOBT, Et3N, DMAP, CH2Cl2, 48 h,
47–67%; (e) Grignard reagent from 4-chloro-1-methyl-piperidine and Mg, LiCl, THF, 54–62%.
Table 1
Effects of central ring substitution on 5-HT1F receptor binding affinity, selectivity and conformation
N
F
ω
H
2
N
O
Ar
O
c
4
t
Compd
Ar
5-HT1F Kia (nM)
5-HT selectivity ratiob
1B/1F
Calcd preferred conformation
D
Ec
xd (ct)
1A/1F
1D/1F
(kcal/mol)
2e
8
12f
18
12e
15
12c
12d
12a
12b
21a
21b
24a
24b
2.1
5.1
8.3
1300
41
5
54
98
Ph
170
NDb
NDb
22
NDb
NDb
NDb
NDb
NDb
1.6
730
NDb
NDb
NDb
NDb
0.2
cis–cis
cis–trans
cis–cis
1.2
0.0
5.1
1.1
5.3
0.0
2.4
0.3
16
0.0
8.1
2.0
9.3
175
176
148
176
176
123
125
136
171
177
164
173
176
2-F-Ph
4-F-Ph
5-F-Ph
6-F-Ph
2-Cl-Ph
2-Me-Ph
2-OMe-Ph
2-OH-Ph
N-2-Py
N-4-Py
N-5-Py
N-6-Py
cis–cis
530
1700
870
610
1100
9.5
2
trans–trans
cis–trans
cis–cis
cis–cis
cis–cis
cis–trans
cis–cis
trans–trans
trans–trans
0.3
NDb
0.5
NDb
91
NDb
4.3
2.5
NDb
3.4
NDb
110
NDb
0.6
ND
NDb
3200
2400
NDb
1
NDb
NDb
2
0.7
0.5
a
Affinities for receptors (expressed as Ki, nM) were determined in vitro by radioligand binding assays using cell lines expressing the appropriate human serotonin
receptors.5,28,29 Each value is the mean of at least two determinations (n P 2). Standard errors were typically within 10% of the mean value.
b
Ratio of the Ki value (derived from at least two determinations) for 5-HT1A, 5-HT1B or 5-HT1D receptor versus the 5-HT1F receptor. ND means the binding affinity at this
receptor was not determined and that less than 50% inhibition was obtained at 10
l
M concentration.
c
D
E = Ect À Elowest, calculated energy difference between the cis–trans (ct) conformation and the lowest energy conformation for any given analog.
d
e
x
is the calculated torsional angel between bond C–C(O)–C(3)–C(4) in the ct conformation.
Data reported from Ref. 20.

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D. Zhang et al. / Bioorg. Med. Chem. Lett. 25 (2015) 4337–4341
ct
cc
tt
tc
Figure 2. Four calculated low-energy conformations of 12f using Gaussian 98 at B3LYP/6-31-G⁄ level.
Table 2
In conclusion, we have demonstrated that the bicyclic indole
nucleus of the 5-HT1F receptor agonist LY334370 (2) can be
replaced by a phenylcarbonyl group. The preferred conformation
of the new series can be enforced by introduction of a fluorine
atom at the 2-position of the central phenyl ring or by replacement
of the phenyl with a 2-pyridine group, providing enhanced selec-
tivity over previous agonist LY334370 (2). Computational analysis
provides further insights into the observed binding and selectivity
results, providing a useful tool for understanding the preferred
conformation for interaction of these analogs with the 5-HT1F
receptor.
5-HT1F receptor efficacy of selected compounds
N
F
H
N
X
O
O
Compd
X
5-HT1F receptor efficacy
EC50 (nM)
Emax (% 5-HT)b
a
8
12f
21a
CH
CF
N
87
55
110
79
85
90
Acknowledgment
a
EC50 for stimulation of [35S]GTP
cS binding in mouse LM(tk-) cells expressing
the cloned human 5-HT1F receptor.30,31 Values are the mean of at least two
We would like to thank Dr. James A. Monn for helpful discus-
sion of the manuscript.
determinations (n P 2). Standard errors were typically within 10% of the mean
value.
b
Maximum stimulation of [35S]GTP
cS binding expressed relative to the maxi-
mum effect of 5-HT.
References and notes
1. Fuller, R. W. Adv. Drug Res. 1988, 17, 349.
energetically most stable conformation. The torsional angel of 176
degree indicates that the ketone C@O is almost co-planar with the
central phenyl ring. Thus, the ct conformation closely resembles
the indole-based conformation of the compound 2 and is presum-
ably the bioactive conformation. Furthermore, this conformation
seems to provide a significant increase in selectivity over other
5-HT receptors. The major driving force for the energy differences
is the electrostatic interactions between 2-F atom with –CONH–
and –CO– bonds. Therefore the energy profiles are different for dif-
ferent patterns of F-substitution. For 4- or 6-F substitution (18 or
15), cc or tt form becomes the most stable conformation, respec-
tively. The energy difference between the most stable conforma-
tion and the bioactive ct conformation is sufficient (>2 kcal/mol)
such that affinity at the 5-HT1F becomes unfavorable. For com-
pounds 12e and 8, cc and ct forms are almost equally stable (with
1 kcal/mol difference), thus they can still adopt the bioactive ct
conformation, retaining reasonable 5-HT1F receptor affinity. In
the case of 12c, electrostatic interactions between 2-Cl and the
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of them were potent 5-HT1F receptor agonists.

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4341
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26. The first word refers to the geometry of the bond (O)C–N–C(1)–C(6) (see
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C–C(O)–C(3)–C(4).
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