New hits as antagonists of GPR103 identified by HTS

Article abstract of DOI:10.1021/ml400519h

Preclinical data indicate that GPR103 receptor and its endogenous neuropeptides QRFP26 and QRFP43 are involved in appetite regulation. A high throughput screening (HTS) for small molecule GPR103 antagonists was performed with the clinical goal to target weight management by modulation of appetite. A high hit rate from the HTS and initial low confirmation with respect to functional versus affinity data challenged us to revise the established screening cascade. To secure high quality data while increasing throughput, the binding assay was optimized on quality to run at single concentration. This strategy enabled evaluation of a larger fraction of chemical clusters and singletons delivering 17 new compound classes for GPR103 antagonism. Representative compounds from three clusters are presented. One of the identified clusters was further investigated, and an initial structure-activity relationship study is reported. The most potent compound identified had a pIC₅₀ of 7.9 with an improved ligand lipophilic efficiency.

Full text of DOI:10.1021/ml400519h

Letter
pubs.acs.org/acsmedchemlett
New Hits as Antagonists of GPR103 Identified by HTS
Anneli Nordqvist,† Lisbeth Kristensson,‡ Kjell E. Johansson,† Krystle Isaksson da Silva,† Tomas Fex,†
Christian Tyrchan,§ Anette Svensson Henriksson,† and Kristina Nilsson*,†
†CVMD Medicinal Chemistry, ‡Discovery Sciences, and §RIA Medicinal Chemistry, AstraZeneca, Pepparedsleden 1, 431 83 Molndal,
̈
Sweden
S
* Supporting Information
ABSTRACT: Preclinical data indicate that GPR103 receptor
and its endogenous neuropeptides QRFP26 and QRFP43 are
involved in appetite regulation. A high throughput screening
(HTS) for small molecule GPR103 antagonists was performed
with the clinical goal to target weight management by
modulation of appetite. A high hit rate from the HTS and
initial low confirmation with respect to functional versus
affinity data challenged us to revise the established screening
cascade. To secure high quality data while increasing throughput, the binding assay was optimized on quality to run at single
concentration. This strategy enabled evaluation of a larger fraction of chemical clusters and singletons delivering 17 new
compound classes for GPR103 antagonism. Representative compounds from three clusters are presented. One of the identified
clusters was further investigated, and an initial structure−activity relationship study is reported. The most potent compound
identified had a pIC50 of 7.9 with an improved ligand lipophilic efficiency.
KEYWORDS: G-protein coupled receptor, high throughput screening, appetite regulation, SP9155, 26RFa, 43RFa, GPCR
receptor activation would promote reduced body weight by
modulation of appetite.
besity is a global epidemic associated with increased
1,2
Omorbidity and mortality.
GPR103 is a family A G-
protein coupled receptor first described in 2001.3 The
endogenous GPR103 neuropeptide ligands QRFP26 and the
N-terminal elongated QRFP43 were discovered by three
different groups4−6 and paired with an, at that time, orphan
receptor GPR103.4,5 QRFP26 and QRFP43 are RFamide
peptides encompassing the C-terminal Arg-Phe-NH2 motif
common to all RFamide family members. Structure−activity
relationships (SAR) studies of QRFP26 show that the terminal
Phe24-Arg25-Phe26 motif7 and the C-terminal amidation
common to the RFamide family are very important for
functional activity.5,7
Antagonists of GPR103 in context of weight management
have previously been published in four different patents
covering indole13−15 and imidazoline16 derivatives. In this
communication we describe an HTS based hit identification of
three novel GPR103 small molecule antagonists structurally
distinct from previously disclosed GPR103 antagonists. A SAR
study with synthetic procedures outlined for one of the most
compelling clusters is presented.
The hit finding strategy for GPR103 antagonists was based
on the HTS of the AstraZeneca proprietary compound
collection. The primary assay in the screening cascade was a
functional assay assessing GPR103 antagonism through
measurements on production of inositol-1-phosphate (IP-1).
Screening of compounds started at single concentration giving
a hit rate of 4.7%. Functional activity was then followed up in a
ten point concentration−response (CR) IP-1 assay leaving 83%
classified as actives. Subsequently compounds were screened in
an orthogonal cell based label free dynamic mass redistribution
(DMR) ten point CR assay, in which 52% were confirmed
active. Finally 100 compounds based on a diverse selection of
the most attractive compounds were tested in a [125I]-QRFP43
radioligand binding (RLB) ten point CR assay with a hit rate of
3%. Despite a high confirmation rate of functional activity, only
a small fraction of compounds considered active in the
Gene expression data show that GPR103 and its endogenous
GPR103 neuropeptide ligands are expressed in ventromedial
nuclei, lateral hypothalamus, and arcuate nucleus, which are
areas known to be involved in the control of feeding behavior
and body weight.4,5,8−10 Peripherally GPR103 is found to be
expressed in heart, kidney, retina, and testis but at considerably
lower levels.4 Preclinical data demonstrate that intracerebro-
ventricular injections (i.c.v.) of the endogenous agonists
QRFP26 and QRFP43,6,10,11 as well as synthetic peptidomi-
metic agonists12 increase feeding in rodents. Also, prepro-
QRFP26 mRNA is up-regulated in the hypothalamus in fasted
mice as well as in ob/ob and in db/db mice compared to fed
mice and wild-type mice.10 High-fat feeding of rats also results
in increased expression of endogenous ligands but does not
alter GPR103 expression. Data taken together points at
GPR103 to have a function in controlling appetite, suggesting
that inhibition of the orexigenic effect from QRFP26/QRFP43
Received: December 17, 2013
Accepted: February 22, 2014
Published: February 22, 2014
© 2014 American Chemical Society
527
dx.doi.org/10.1021/ml400519h | ACS Med. Chem. Lett. 2014, 5, 527−532

ACS Medicinal Chemistry Letters
Letter
functional assays were confirmed in the RLB assay. This low
confirmation rate could have several reasons, e.g., due to the
lack of a technology artifact assay in IP-1, binding to allosteric
sites of GPR103, or IP-1 production through interaction with
other protein targets. To ensure high quality starting points for
the chemistry program, we therefore needed to assess a larger
part of the chemical space of the HTS output by affinity
screening in the [125I]-QRFP43 RLB assay.
Table 1. Cluster Representatives from the HTS
The throughput of the original [125I]-QRFP43 96-well
format RLB assay ten point CR setup was hampered by high
cost per well, amount of radioactive waste, and by variability in
quality control parameters. Hence, when affinity data became
critical for project progression the RLB assay quality had to be
improved to allow counter screening of a larger set of
compounds in single concentration screening and thereby
increase the throughput. This was achieved by the transfer of
larger volumes of the assay reaction to the filter plate. This step
was performed by an automated filtration step in a Biomek FX
(Beckman Coulter) where the assay reaction is transferred to a
filter plate and all wells in the plate are washed simultaneously
with ice-cold wash buffer under vacuum to remove all unbound
radioligand. By further optimizing the number of wash cycles
and the height of the Biomek FX tip head over the filter plate
during washing, the background radioactivity was decreased,
thus increasing the assay window. This was reflected by the Z′
values increasing from 0.2−0.3 to 0.5−0.9 (average 0.76 0.11,
mean 0.76, n = 24). The quality of the improved assay was
controlled with 29 GPR103 reference compounds previously
confirmed in functional and affinity screening.
By revisiting all compounds flagged as active in IP-1 single
concentration in the HTS and in ten point CR, 963 compounds
were selected for screening in the [125I]-QRFP43 RLB assay
single concentration to give a mean inhibition of radioligand
binding in percent at 10 μM ligand concentration. The
compounds considered active, 12.8%, were subsequently
followed up in RLB ten point CR. The accuracy of the single
concentration RLB assay was 83% calculated as (TP + TN)/
(TP + TN + FP + FN), as confirmed in ten point CR RLB.
This approach enlarged the set of confirmed GPR103
antagonists and enabled us to identify in all 17 new chemical
clusters of which representatives from three of the clusters are
depicted in Table 1. From a SAR perspective, these structures
are novel with respect to chemical similarity compared with
previously known GPR103 antagonists. A common feature of
the presented clusters in Table 1 is their basic functionality with
pKa ranging from 8.1−10.5, also observed in the endogenous
agonists5−7 as well as in pseudopeptide agonists.12,19 Two of
the identified cluster representatives (2 and 3, Table 1) have
previously been reported in the context of ligands for
GPCRs.17,18 Compound 1 showed compelling in vitro data
on GPR103 antagonism as well as potential for exploration and
was selected as a starting point for chemistry. Full IC50 curves
for IP-1 and RLB assays of compound 1 are depicted in Figures
S1 and S2 in the Supporting Information.
a
pIC50 is reported as mean SD, n = 2 − 4 from ten point CR with
b
the number of experiments in parentheses. Number of cluster
members with pIC50 > 5 in IP-1 after HTS.
followed by reaction with cyclopentanethiol and reduction of
the nitro group to give 6. The resulting aniline was reacted with
selected nitriles to give the desired amidines (1, 7a−7k).
Amidine aryl and alkyl analogues to compound 1 (7a−7k,
Scheme 1, Table 2) display a broad SAR. The thiophene-3-yl
regioisomer (7a), the phenyl-analogue (7b), 4- or 5-substituted
thiophene (7c−7e), or the para-chlorophenyl analogue (7f) are
equipotent or more potent compared to the thiophen-2-yl hit
(1) with pIC50 in the range of 6.8−7.9. Replacing the thiophene
with the more polar, electron poor thiazole (7i) or para-
pyridine (7j) gave marked reduction in potency. However,
introducing a meta-pyridine (7k) gains back some of the
potency compared to 7i and 7j, while keeping logD7.4 at 2.6. A
striking drop in or loss of IP-1 activity was seen in benzyl- and
ethyl-matched pairs to compound 1, 7g (pIC50 5.2) and 7h
(pIC50 <4.4) respectively, suggesting that the amidine aryl
group should be directly adjacent to the amidine.
Variations of the amidine functional group (II) in compound
1 were introduced by coupling 6 with thiophene-2-carboxylic
acid to give the amide analogue (8) or with 2-fluoropyridine to
give the 2-aminopyridine analogue (10, Scheme 1). The
amidine functionality was further modulated by mono-N- and
di-N,N-methylation starting from the thiophene carboxamide 8.
Compound 8 was transformed to the corresponding
carbothioamide using Lawesson reagent and then N-alkylated
by reaction with methyl amine to give mono-N-methylated 9a
and di-N,N-methylated compound 9b (Scheme 1).
From SAR exploration modulating the amidine, it is evident
that a positive charge on the amidine is a hot-spot for targeting
GPR103 antagonism also consistent with the pKa properties of
the hit compounds (2 and 3). By replacing the amidine with
the corresponding amide (8) or the 2-aminopyridyl analogue
(10), the compounds drop 2 orders of magnitude in potency
compared to the original amidine hit (1). Also, methylation of
the imine nitrogen of the amidine (9a) leads to one log unit
drop in functional activity, whereas methylation of both the
amidine nitrogens (9b) abolishes functional activity (Table 2).
To build SAR around the core structure of compound 1
(Table 2, see Supporting Information for Table 2 with
structures drawn) the following parts were modified: (I) the
amidine aryl group, (II) the amidine functionality, (III) the
methoxy substituent, and (IV) the cyclopentylsulfanylmethyl
group (Schemes 1−5).
Exploration of the amidine aryl group (I) in the hit
compound 1 (Scheme 1), was started with bromomethylation
of the commercially available 4-methoxy-nitrobenzene (4)
528
dx.doi.org/10.1021/ml400519h | ACS Med. Chem. Lett. 2014, 5, 527−532

ACS Medicinal Chemistry Letters
Letter
started from commercially available 4-chloro-2-(chloro-meth-
yl)-1-methoxy-benzene (12), which was reacted with cyclo-
pentanethiol, followed by formation of the corresponding
benzonitrile and finally amidation to give the desired reversed
amidine 15. Compound 15 drops 1 order of magnitude in
activity (Table 2) and indicates that the topology around the
positive charge is sensitive.
Table 2. Functional Activity and Radioligand Binding for
Analogues of Compound 1 and Their Measured logD7.4
The SAR exploration was continued at the methoxy position
(III, Scheme 3, 18a−18e). Reacting 16 with cyclopentanethiol
followed by reduction of the nitro group gave aniline
intermediate 17a. The methyl substituted aniline (17b) was
synthesized from 19 by reduction of the carboxylic acid
followed by halogenation, reaction with cyclopentanethiol, and
reduction of the nitro group. The halo substituted inter-
mediates 17c and 17d were synthesized from 2-fluoro or 2-
chloro-5-nitrobenzaldehyde (21a and 21b), respectively, by
reduction of the aldehyde and subsequent reduction of the
nitro group followed by Boc protection of the resulting aniline.
Compounds 22a and 22b were converted to the corresponding
bromides, which were then reacted with cyclopentanethiol, and
after Boc deprotection the aniline intermediates 17c and 17d
were obtained. Nitration of 2- trifluoromethoxybenzaldehyde
(23) followed by reduction of the aldehyde gave the alcohol 24.
Treatment of the alcohol with methanesulfonyl chloride,
subsequent reaction with cyclopentanethiol, and finally
reduction of the nitro group gave aniline 17e. Aniline
intermediates (17a−17e) were reacted with methyl thio-
phene-2-carboximidothioate to give the desired amidine
analogues (18a−18e, Scheme 3). Read-out from the IP-1
assay clearly suggest a steep SAR as all of the methoxy-
replacements lost at least 1 order of magnitude as compared to
1 (Table 2).
The final SAR assessment was performed at the cyclo-
pentylsulfanylmethyl group (IV). Sulfur was replaced by
classical bioisosters21 as −O− or −CH2− giving compounds
27 and 29, respectively (Scheme 4). Synthesis of compound 27
started with bromomethylation of 4 to give 25, which after
nucleophilic substitution with cyclopentanol furnished the ether
(26). Reduction of the nitro group and reaction with methyl
thiophene-2-carboximidothioate yielded compound 27. The
carbon analogue (29) was synthesized from 25 by a Wittig
reaction, followed by simultaneous reduction of the nitro group
and the double bond using H2(g) and subsequent reaction with
methyl benzenecarboximidothioate. The nonclassical sulfur
bioisosteres21 −SO− and −SO2− (11a and 11b, respectively,
Scheme 1) were accomplished by oxidation of 7b using 3-
chlororbenzoperoxoic acid. Out of the synthesized bioisosteres
(27, 29, 11a, and 11b), only the carbon analogue (29, pIC50
6.5) retained some potency but still lost 1.2 log units compared
to 7b (Table 2).
To challenge polarity, sulfur was replaced by an amide bond
exemplified by compound 34 (Scheme 5). The starting material
(32) was coupled with cyclopentane-carboxylic acid to give the
nitrobenzene intermediate (33), which after standard reduction
of the nitro group and reaction with benzonitrile yielded
compound 34. The increase in polarity (logD7.4 = 1.1, ΔlogD7.4
= 1.4) was accompanied with an even more pronounced
decrease in potency (ΔpIC50 = 2.1) compared to the sulfur
analogue 7b (Table 2).
IP-1 data from exploration of the aliphatic cyclopentyl ring
suggest a tight SAR also in this region. Nine aryl analogues
(data not shown) were made, which all display a potency of 1
μM or less, here exemplified with the phenyl analogue (31,
a
pIC50 is reported as mean SD, n = 2−4 from ten point CR with the
b
number of experiments in parentheses. LLE was calculated as LLE =
pIC50 − logD7.4.20
To further investigate the amidine functionality (II) the
reversed amidine (15, Scheme 2) was synthesized. Synthesis
529
dx.doi.org/10.1021/ml400519h | ACS Med. Chem. Lett. 2014, 5, 527−532

ACS Medicinal Chemistry Letters
Letter
a
Scheme 1
a
Reagents and conditions: (a) CHO, H2SO4, NaBr, HOAc, 85 °C; (b) cyclopentanethiol, K2CO3, DMF; (c) iron dust, HOAc, 60 °C; (d) R1−CN,
AlMe3, toluene, 95 °C or ethylmagnesium bromide, THF or AlCl3, 1,2-dichlororethane, 115 °C; (e) thiophene-2-carboxylic acid, EDC, HOBt, TEA,
DMF; (f) 2-fluoropyridine, Cs2CO3, DMA, 200 °C; (g) R1 = benzenecarboximidoyl, 3-chlorobenzoperoxoic acid, DCM; (h) Lawesson reagent,
toluene, 80 °C; (i) MeNH2, MeOH, 50 °C; (j) NaH, MeI, THF, 0 °C.
a
a
Scheme 2
Scheme 3
a
Reagents and conditions: (a) cyclopentanethiol, K2CO3, DMF; (b)
Zn, Zn(CN)2, XPhos, Pd2(dba)3, DMA, 150 °C; (c) aniline, AlMe3,
toluene, 95 °C.
Scheme 4 and Table 2). Compound 31 was synthesized from
25 by reaction with benzenethiol, followed by reduction of the
nitro group using iron dust and reaction of the aniline
intermediate with benzonitrile.
Encouraging for this series originating from compound 1,
SAR revealed no consistent correlation between potency and
lipophilicity (Table 2). A higher lipophilic ligand efficiency
(LLE) indicates less lipophilic contribution to potency and is
therefore a suitable way to rank lead compounds.20 For the best
compound (7b), LLE could be increased to 5.2. For 20 of the
compounds presented in Table 2, GPR103 activity was
confirmed in RLB. A good correlation between functional
and binding data for these ligands was observed (see
Supporting Information, Figure S3).
In summary, an HTS was run with 900,000 compounds
targeting GPR103 using an IP-1 assay. After functional
screening in IP-1 single concentration and ten point CR
followed by orthogonal screening in DMR, the most active and
interesting clusters were followed up in a [125I]-QRFP43 RLB
ten point CR assay. A low confirmation rate with respect to
functional versus affinity data from screening of the initial hit
clusters was observed. This led to a revision of the screening
cascade to enable affinity screening of a larger set of
a
Reagents and conditions: (a) cyclopentanethiol, K2CO3 or Cs2CO3
or NaOH, DMF or MeOH; (b) iron dust, HOAc or NH4Cl, 60 °C;
(c) BH3, THF, 30 °C; (d) PBr3, DCM, 0 °C; (e) NaBH4, THF,
MeOH, 0 °C; (f) Boc2O, DMF, 60 °C; (g) PPh3, NBS; (h) HCl; (i)
H2SO4, HNO3, 0 °C; (j) TEA, DCM, methanesulfonyl chloride; (k)
methyl thiophene-2-carboximidothioate, i-propanol, 85 °C or
thiophene-2-carbonitrile, AlMe3, toluene, 95°.
compounds and secure project progression. The [125I]-
QRFP43 RLB assay ten point CR assay was optimized to run
in single concentration to enable a larger number of chemical
clusters and singletons to be evaluated. This lead to the
discovery of several chemically diverse compounds acting as
GPR103 antagonists. Herein three new chemical entities
530
dx.doi.org/10.1021/ml400519h | ACS Med. Chem. Lett. 2014, 5, 527−532

ACS Medicinal Chemistry Letters
Letter
a
Scheme 4
AUTHOR INFORMATION
Corresponding Author
*(K.A.N.) Tel: +46 31 7762426. Fax: +46 31 7763700. E-mail:
kristina.a.nilsson@astrazeneca.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to thank Bryan Egner for synthesis of 2-
hydroxy-5-nitro-benzaldehyde. We would also like to thank the
■
Separation Science Group at AstraZeneca Molndal for help
̈
with compound purification.
ABBREVIATIONS
■
CR, concentration response; DIEA, ethyldiisopropylamine;
DMR, dynamic mass redistribution; EDC, 3-(ethylimino-
methylene-amino)-N,N-dimethyl-propan-1-amine; GPR103,
pyroglutamylated RF amide peptide receptor 103; HOAc,
acetic acid; HOBt, 1-hydroxybenzotriazole; IP-1, inositol-1-
phosphate; LLE, lipophilic ligand efficiency; logD7.4, logarithm
of the distribution coefficient measured at pH 7.4; RLB, radio
ligand binding; TBTU, 2-(1H-benzo[d][1,2,3]triazol-1-yl)-
1,1,3,3-tetramethyl-isouronium tetrafluoroborate; TEA, triethyl-
amine
a
REFERENCES
Reagents and conditions: (a) CHO, H2SO4, NaBr, HOAc, 85 °C; (b)
■
cyclopentanol, t-BuOK, THF, 50 °C; (c) PPh3, DMF, 100 °C; (d)
cyclopentanecarbaldehyde, t-BuOK, THF, 0 °C; (e) Pd/C, H2(g),
MeOH, 25 °C; (f) benzenethiol, K2CO3, DMF; (g) iron dust, HOAc,
70 °C; (h) methyl thiophene-2-carboximidothioate, i-propanol, Δ; (i)
methyl benzenecarboximidothioate, i-propanol, 88 °C; (j) benzoni-
trile, AlMe3, toluene, 95 °C.
(1) Finucane, M. M.; Stevens, G. A.; Cowan, M. J.; Danaei, G.; Lin, J.
K.; Paciorek, C. J.; Singh, G. M.; Gutierrez, H. R.; Lu, Y.; Bahalim, A.
N.; Farzadfar, F.; Riley, L. M.; Ezzati, M. National, regional, and global
trends in body-mass index since 1980: systematic analysis of health
examination surveys and epidemiological studies with 960 country-
years and 9.1 million participants. Lancet 2011, 377, 557−67.
(2) Nguyen, D. M.; El-Serag, H. B. The epidemiology of obesity.
Gastroenterol. Clin. North Am. 2010, 39, 1−7.
a
Scheme 5
(3) Lee, D. K.; Nguyen, T.; Lynch, K. R.; Cheng, R.; Vanti, W. B.;
Arkhitko, O.; Lewis, T.; Evans, J. F.; George, S. R.; O’Dowd, B. F.
Discovery and mapping of ten novel G protein-coupled receptor
genes. Gene 2001, 275, 83−91.
(4) Jiang, Y.; Luo, L.; Gustafson, E. L.; Yadav, D.; Laverty, M.;
Murgolo, N.; Vassileva, G.; Zeng, M.; Laz, T. M.; Behan, J.; Qiu, P.;
Wang, L.; Wang, S.; Bayne, M.; Greene, J.; Monsma, F., Jr; Zhang, F.
L. Identification and characterization of a novel RF-amide peptide
ligand for orphan G-protein-coupled receptor SP9155. J. Biol. Chem.
2003, 278, 27652−27657.
(5) Fukusumi, S.; Yoshida, H.; Fujii, R.; Maruyama, M.; Komatsu, H.;
Habata, Y.; Shintani, Y.; Hinuma, S.; Fujino, M. A new peptidic ligand
and its receptor regulating adrenal function in rats. J. Biol. Chem. 2003,
278, 46387−46395.
a
Reagents and conditions: (a) cyclopentanecarboxylic acid, TBTU,
DIEA, DMF/DCM, 0 °C−rt; (b) iron dust, HOAc, 60 °C; (c)
benzonitrile, AlMe3, toluene, 95 °C.
(6) Chartrel, N.; Dujardin, C.; Anouar, Y.; Leprince, J.; Decker, A.;
Clerens, S.; Do-rego, J.; Vandesande, F.; Llorens-Cortes, C.;
Costentin, J.; Beauvillain, J.; Vaudry, H. Identification of 26RFa, a
hypothalamic neuropeptide of the RFamide peptide family with
orexigenic activity. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 15247−
15252.
(7) Le Olivier, M.; Neveu, C.; Lefranc, B.; Dubessy, C.; Boutin, J. A.;
Do-Rego, J.; Costentin, J.; Tonon, M.; Tena-Sempere, M.; Vaudry, H.;
Leprince, J. Structure−activity relationships of a series of analogues of
the RFamide-related peptide 26RFa. J. Med. Chem. 2011, 54, 4806−
4814.
structurally distinct from disclosed GPR103 antagonists13−16
are reported. For one of the hits, N-[3-(cyclopentylsulfanyl-
methyl)-4-methoxy-phenyl]thiophene-2-carboximidamide (1),
we present SAR exploration resulting in the finding of structural
features important for the activity of this compound class.
ASSOCIATED CONTENT
■
S
* Supporting Information
(8) Bruzzone, F.; Lectez, B.; Alexandre, D.; Jegou, S.; Mounien, L.;
Tollemer, H.; Chatenet, D.; Leprince, J.; Vallarino, M.; Vaudry, H.;
Chartrel, N. Distribution of 26RFa binding sites and GPR103 mRNA
in the central nervous system of the rat. J. Comp. Neurol. 2007, 503,
573−591.
Figures S1, S2 and S3, an enlarged version of Table 2 with
structures drawn in the table, detailed information on synthetic
procedures, and characterization of compounds as well as
description of biological assays associated with this communi-
cation. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) Chartrel, N.; Alonzeau, J.; Alexandre, D.; Jeandel, L.; Alvear-
Perez, R.; Leprince, J.; Boutin, J.; Vaudry, H.; Anouar, Y.; Llorens-
531
dx.doi.org/10.1021/ml400519h | ACS Med. Chem. Lett. 2014, 5, 527−532

ACS Medicinal Chemistry Letters
Letter
Cortes, C. The RFamide neuropeptide 26RFa and its role in the
control of neuroendocrine functions. Front. Neuroendocrinol. 2011, 32,
387−397.
(10) Takayasu, S.; Sakurai, T.; Iwasaki, S.; Teranishi, H.; Yamanaka,
A.; Williams, S. C.; Iguchi, H.; Kawasawa, Y. I.; Ikeda, Y.; Sakakibara,
I.; Ohno, K.; Ioka, R. X.; Murakami, S.; Dohmae, N.; Xie, J.; Suda, T.;
Motoike, T.; Ohuchi, T.; Yanagisawa, M.; Sakai, J. A neuropeptide
ligand of the G protein-coupled receptor GPR103 regulates feeding,
behavioral arousal, and blood pressure in mice. Proc. Natl. Acad. Sci.
U.S.A. 2006, 103, 7438−7443.
(11) Jean-Claude, R.; Leprince, J.; Chartrel, N.; Vaudry, H.;
Costentin, J. Behavioral effects of 26RFamide and related peptides.
Peptides 2006, 27, 2715−2721.
(12) Neveu, C.; Lefranc, B.; Tasseau, O.; Do-Rego, J.; Bourmaud, A.;
Chan, P.; Bauchat, P.; Marec, O. L.; Chuquet, J.; Guilhaudis, L.;
Boutin, J. A.; Segalas-Milazzo, I.; Costentin, J.; Vaudry, H.; Baudy-
Floc’h, M.; Vaudry, D.; Leprince, J. Rational design of a low molecular
weight, stable, potent, and long-lasting GPR103 aza-beta3-pseudopep-
tide agonist. J. Med. Chem. 2012, 55, 7516−7524.
(13) Haga, Y.; Mizutani, S.; Sato, N. Preparation of indole-2-
carboxamide derivatives as QRFP receptor (GPR103) antagonists.
WO2010126164A1, 11/040, 2010.
(14) Fujimura, T.; Kishino, H.; Mizutani, T.; Sakuraba, S.; Sasaki, T.;
Sato, N. Preparation of (hetero)aryl-substituted indolecarboxamides as
GPR103 antagonists. WO2010119984A1, 10/21, 2010.
(15) Kishino, H.; Mizutani, S.; Sakuraba, S.; Sato, N. Preparation of
aryl indole derivatives as human QRFP receptor (GPR103)
antagonists. WO2010117085A1, 10/14, 2010.
(16) Haga, Y.; Moriya, M.; Takahashi, T. Preparation of arylimidazo-
line for use as antiobesity agents. WO2010123150A1, 10/28, 2010.
(17) Nordvall, G.; Petersson, C.; Rakos, L.; Sohn, D. Novel 8-
sulfonyl-3-amino-substituted chroman or tetrahydronaphthalene de-
rivatives modulating the 5-HT6 receptor and their preparation and
pharmaceutical compositions. WO2006126938A1, 11/30, 2006.
(18) Webb, T. R.; Lvovskiy, D.; Kim, S.; Ji, X.; Melman, N.; Linden,
J.; Jacobson, K. A. Quinazolines as adenosine receptor antagonists:
SAR and selectivity for A2B receptors. Bioorg. Med. Chem. 2003, 11,
77−85.
(19) Pierry, C.; Couve-Bonnaire, S.; Guilhaudis, L.; Neveu, C.;
Marotte, A.; Lefranc, B.; Cahard, D.; Segalas-Milazzo, I.; Leprince, J.;
Pannecoucke, X. Fluorinated pseudopeptide analogues of the neuro-
peptide 26RFa: synthesis, biological, and structural studies. Chem-
BioChem 2013, 14, 1620−1633.
(20) Leeson, P. D.; Springthorpe, B. The influence of drug-like
concepts on decision-making in medicinal chemistry. Nat. Rev. Drug
Discovery 2007, 6, 881−890.
(21) Meanwell, N. A. Synopsis of some recent tactical application of
bioisosteres in drug design. J. Med. Chem. 2011, 54, 2529−2591.
532
dx.doi.org/10.1021/ml400519h | ACS Med. Chem. Lett. 2014, 5, 527−532