Privileged structure-based ligands for melanocortin receptors - Tetrahydroquinolines, indoles, and aminotetralines

Article abstract of DOI:10.1016/j.bmcl.2005.07.035

Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1. Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1.

Full text of DOI:10.1016/j.bmcl.2005.07.035

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4459–4462
Privileged structure-based ligands for melanocortin
receptors—tetrahydroquinolines, indoles, and aminotetralines
Matthew J. Fisher,* Ryan T. Backer, Saba Husain, Hansen M. Hsiung,
Jeffrey T. Mullaney, Thomas P. OÕBrian, Paul L. Ornstein, Roger R. Rothhaar,
John M. Zgombick and Karin Briner
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46258, USA
Received 3 June 2005; revised 12 July 2005; accepted 12 July 2005
Available online 19 August 2005
Abstract—Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines
produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1.
Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as
the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1.
Ó 2005 Elsevier Ltd. All rights reserved.
Cl
Cl
Melanocortins are a family of bioactive peptides derived
from the post-translational modification of proopiomel-
anocortin (POMC).1 These substances, whose properties
were first described in 1916,2 are known to possess a fas-
cinating array of physiological functions. Recently, five
unique type I G-protein coupled receptors (GPCRs)
have been identified and cloned for these peptide li-
gands.3 While use of the Melanocortins as pharmacolog-
ical tools has afforded considerable insight into the
functions of each receptor, complete characterization
of each member has been hampered by the lack of selec-
tive tools.4
O
O
O
O
N
N
H
H
H
N
N
N
HN
OH
HN
3 "Dipeptide
address element"
N
NHSO2Me
NHSO2Me
1
2 "Privileged structure"
HMC4 Ki 0.22
M
Figure 1.
We have recently described our library-based approach
for the generation of ligands for the melanocortin recep-
tors.5 This effort initially yielded structures of modest
potency and selectivity, which were readily optimized
for the Human Melanocortin receptor 4 (hMC4). The
lead compound (1) can be described as being composed
of a GPCR privileged structure6 (2) coupled with a
dipeptide Ôaddress elementÕ 3 (Fig. 1). Consistent with
the literature, we found that optimization of these types
of structures benefited from chemical modification of
the privileged structure to a greater extent than the
address element.7 This strategy was enhanced further
by the fact that our moleculesÕ key components were
linked together with an amide bond, thus allowing ready
exchange of a variety of privileged structures. Herein, we
describe a portion of our efforts to develop and under-
stand new privileged structures that afford melanocortin
receptor activity when coupled to the previously
described dipeptide address element 3. Inspection of
the privileged structure contained in our lead compound
reveals functionality common to other similar motifs;
namely, an aryl group and an amine-based polar group.8
We sought to explore the relationship of these two
key elements by constraining the polar group in lead
compound 1. Specifically, we sought to see if the aryl
Keywords: Melanocortin receptors; Privileged structures.
*
Corresponding author. Tel.: +1 3172760632; fax: +1 3174333666;
e-mail: fisher_matthew_j@lilly.com
Deceased.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.035

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M. J. Fisher et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4459–4462
sulfonamide could be replaced with suitably substituted
tetrahydroquinolines, indoles, and aminotetralines.
indolene 12. Sulfonamide 13 is readily obtained from
this material by exposure to methanesulfonyl chloride.
Deprotection of 12 and 13 is easily accomplished by
treatment with TFA, affording compounds 14 and 15.
Preparation of the desired isoquinoline intermediates
begins by allowing 8-bromoisoquinoline9 (4) to react
with excess piperazine in the presence of palladium10
(Scheme 1). The resulting adduct was protected on the
secondary nitrogen with Boc2O and then partially re-
duced with Pt2O, affording tetrahydroisoquinoline 5.
The formed amine was then transformed further either
by reductive amination or acylation. Removal of the
Boc group from the piperazine was accomplished with
TFA. Intermediates containing either an 8-substituted
tetrahydroquinoline (6) or a 5-substituted tetrahydroiso-
quinoline (7) were prepared from the corresponding
bromoquinoline derivatives in a similar fashion.
Substituted 2-aminotetralines were prepared in several
ways, as outlined in Scheme 3. In general, 2-amino-8-
bromotetralines were coupled with Boc-protected piper-
azine to form intermediate 16 using the Buchwald
conditions described previously. Removal of the Boc
group from the piperazine afforded amines 17. Racemic
2-aminotetralines were prepared either by reductive ami-
nation of ketone 18 or by a routine acylation or alkyl-
ation of amine 19. Optically active aminotetralines
were prepared from the known bromotetraline 20.11
Final compounds for this paper were constructed by
coupling the aforementioned piperazine intermediates
with the known dipeptide address element 3. A specific
example of this sequence is illustrated with the reaction
of intermediate 15 and the previously described dipep-
tide 3 in the presence of HATU12 to afford the penulti-
mate derivative 21. Treatment with TFA provided the
desired deprotected compound 22d, which could be used
as the corresponding TFA salt or subjected to salt ex-
change to obtain the HCl salt (Scheme 4). Coupling of
racemic aminotetralines with dipeptide 3 afforded dia-
stereomeric pairs that were not separated for biological
evaluation.
Compounds containing a substituted indole or indolene
were prepared from protected indole 8, as outlined in
Scheme 2. The reaction of Boc-protected piperazine with
8 in the presence of palladium affords intermediate 9,
which, upon exposure to TFA, affords amine 10. Repro-
tection of the piperazine nitrogen in 10 yields indole 11,
which is then reduced with NaBH3CN providing
Boc
N
Br
N
a,b,c
N
NH
X
N
5
4
N
Br
H
H
N
NR1R2
NR1R2
N
a
N
N
R
16 X = Boc
17 X = H
N
b
NR
Br
Br
Br
H
O
NH2
N
7
6
Scheme 1. Reagents: (a) Piperazine, Pd(dba)2, NaOAc, BINAP; (b)
Boc2O; (c) Pt/H2.
18
19
20
Scheme 3. Reagents: (a) Boc piperazine, Pd(dba)2, NaOMe, BiNap;
(b) HCl.
R
N
Br
N
Boc
N
Boc
N
a
Cl
Cl
8
9
R = Boc
O
b
O
10 R = H
Boc
N
H
N
Boc
N
O
O
N
H
N
N
a
H
H
OH
BocN
N
N
RN
N
N
N
+
R
R
N
H
3a
N
c
e
N
N
SO2CH3
N
SO2CH3
N
11
12 R = H
13 R = SO2Me
14 R = H
15 R = SO2Me
d
15
21
R
=
=
Boc
H
b
22d R
Scheme 2. Reagents: (a) Boc piperazine, Pd(dba)2, NaOAc, BINAP;
(b) TFA; (c) NaBH3CN; (d) MeSO2Cl; (e) HCl.
Scheme 4. Reagents: (a) HATU, (b) TFA or HCl.

M. J. Fisher et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4459–4462
4461
Compounds synthesized for this study were evaluated
for binding affinity, across human melanocortin recep-
tors 1, 3, 4, and 5, by determining the competitive inhi-
bition of [125I]NDP MSH binding.13,14 Compound
specific data obtained with these assays are given in
Tables 1–3.
acyclic congener 1. Exchange of the sulfonyl group with
an acetyl moiety (22b) resulted in further erosion of
activity (7.7 lM Ki). The nonsubstituted compound
(22a) had similar potency (1.6 lM) as the acetyl analog.
Contracting the nitrogen-containing ring by one atom
provided indolene 22d, which has similar activity
(0.94 lM) as the tetrahydroquinoline 22c. A comparison
of compounds 22e and 22f suggests that unsaturation in
the 5-membered ring had little impact on activity. Sur-
prisingly, the sulfonyl-capped isoquinoline analog 22h
was 2-fold more potent than its tetrahydroquinoline
analog 22c. Interestingly, in this series, the acetyl and
sulfonyl groups provide similar activities (compare 22g
and 22h with 22b and 22c). Changing the polar group
from acetyl to N-alkyl had a positive impact in this ser-
ies, as exemplified by compounds 22k and 22l, which
displayed binding affinities more potent than our lead,
compound 1. Isomeric isoquinoline analogs 22m and
22n were in each case less potent than there direct com-
parators 22h and 22l, respectively.
Tetrahydroquinoline derivatives 22a–c, which represent
direct cyclic analogs of our lead compound 1, were the
first series examined (see Table 1). The sulfonyl substi-
tuted analog 22c afforded 3.8-fold less potency than its
Table 1. Fused heterocycle analogs 22a–n
Privileged structure
Compound
R
hMC4R (lM)
Ki13,15
22a
22b
22c
H
1.6
7.7
0.9
R
N
COCH3
SO2CH3
R
N
22d
22e
SO2CH3
H
0.9
2.1
Replacement of the amine moiety in these tetrahydro-
quinoline analogs with a methylene provides tetraline
derivative 22o16 (Table 2), which is significantly less ac-
tive (4.2 lM) than any analog in the above series. Addi-
tion of a substituted amine to the tetraline ring of 22o
affords analog 22p, which has a Ki of 0.24 lM. Primary
amide 22q was 2-fold less active (0.41 lM) than amine
22p and similar in activity to tertiary sulfonamide 22r
(0.53 lM). In contrast to the aforementioned amide
derivatives, alkylation of the amine appeared to provide
better activity. For example, relative to primary amine
22p, monomethylation (22s) increased affinity slightly
(0.15 lM), and dimethylation (22t) afforded a 4-fold in-
crease in activity (0.07 lM). The diethyl (22u) and the
dipropyl analogs (22v) were similar in activity with KiÕs
of 0.17 and 0.14 lM, respectively. Cyclic amines (22w
and 22x) did not appear to provide any advantage rela-
tive to their dialkyl counterparts. Compounds 22y and
22z illustrate the activity contribution of each diastereo-
mer of the diethyl analog. The R containing enantiomer
22y was modestly more potent (0.05 lM) than the S
containing enantiomer 22z (0.08 lM).
H
N
22f
—
4.8
22g
22h
22i
22j
22k
22l
COCH3
SO2CH3
SO2iPr
SO2Ph
CH3
0.5
0.6
NR
NR
0.95
2.5
0.28
0.19
CH2CH3
22m
22n
CH2CH3
SO2CH3
0.7
3.9
Table 2. Tetraline analogs 22o–z
R
Compound
R
hMC4 (lM) Ki13,15
22o
22p
22q
22r
22s
22t
H
NH2
4.2
0.24
0.41
0.53
0.15
0.07
0.17
0.18
0.14
0.23
0.05
0.08
NHAc
In addition to MC4 activity, compounds were screened
for binding affinity at human melanocortin receptors
1, 3, and 5. Data for select compounds, which represent
the selectivity trends, observed for the series of com-
pounds described above, are given in Table 3. In gener-
al, the compounds we prepared were inherently selective
for MC4, with the greatest selectivity ratios seen be-
tween MC1 and MC3 (ꢀ20-fold). Selectivity between
MC4 and MC5 was modest, favoring the former rough-
ly by 3-fold. Selectivity for MC5 versus MC1 and MC3
was slightly less than that observed for MC4 with aver-
age ratios of 5- to 10-fold. Compounds with selectivity
for MC1 or MC3 were not observed for the series
reported in this paper.
N(CH3)SO2CH3
NHCH3
N(CH3)2
N(CH2CH3)2
22u
22v
22w
22x
22y
22z
N(CH2CH2CH3)2
N(CH2)4
N(CH2)2O
R (NCH3)2
S (NCH3)2
Table 3. Representative binding selectivities
Compound
Ki (lM) (Fold selectivity relative to MC4)
hMC113,15
hMC313,15
hMC513,15
22b
22j
20 (23)
7 (23)
4 (72)
3 (47)
0.5 (0.6)
1.2 (4)
4.0 (5)
The data highlighted in this report demonstrate that fused
ring systems, which incorporate separate aromatic and
polar functionalities, can be employed as privileged
structures in this series. Within the constrained analogs
0.7 (2.6)
0.28 (5.6)
0.26 (3.8)
22t
22o
8.2 (164)
1.2 (181)

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M. J. Fisher et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4459–4462
Cashen, D. E.; Drisko, J. E.; Hom, G. J.; Howard, A.
D.; MacIntyre, D. E.; van der Ploeg, L. H. T.; Patchett, A.
A.; Nargund, R. P. J. Med. Chem. 2002, 45, 4589; (c)
Dyck, B.; Parfker, J.; Phillips, T.; Carter, L.; Murphy, B.;
Summers, R.; Hermann, J.; Baker, T.; Cismowski, M.;
Saunders, J.; Goodfellow, V. Biorg. Med. Chem. Lett.
2003, 13, 3793; (d) Jhang, J.; Xiong, C.; Ying, J.; Wamg,
W.; Hrubt, V. J. Org. Lett. 2003, 5, 3115; (e) Fotsch, C.;
Smith, D. M.; Adams, J. A.; Cheetham, J.; Croghan, M.;
Dorhety, E. M.; Hale, C.; Jarosinski, M. A.; Kelly, M. G.;
Norman, M. H.; Tamayo, N. A.; Xi, N.; Baumgartner, J.
W. Biorg. Med. Chem. Lett. 2003, 13, 2337.
prepared, we noticed sensitivity in regard to placement
and type of the polar group. Locating the polar group
adjacent to the aromatic ring apparently afforded too
much conformational restraint, resulting in lower affinity,
relative to its acyclic congener. This activity was
somewhat restored by moving the polar group one atom
over to the benzylic position. Further movement within
the ring proved to be less optimal. Movement of the polar
group from an endocyclic to an exocyclic position
presumably provided additional conformational flexibil-
ity, which leads to an increase in activity. Interestingly, in
the one example shown, enantiomeric configuration
had little impact on overall activity. Consistent with
earlier findings, activity was higher with alkyl amine
substitution.5
5. Richardson, T. I.; Ornstein, P. L.; Briner, K.; Fisher, M.
J.; Backer, R. T.; Biggers, C. K.; Clay, M. P.; Emmerson,
P. J.; Hertel, L. W.; Hsiung, H. M.; Husain, S.; Kahl, S.
D.; Lee, J. A.; Lindstrom, T. D.; Martinelli, M. J.; Mayer,
J. P.; Mullaney, J. T.; OÕBrien, T. P.; Pawlak, J. M.;
Revell, K. D.; Shah, J.; Zgombick, J. M. J. Med. Chem.
2004, 47, 744.
6. Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber,
D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.;
Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
7. For examples of this phenomenon, compare the ligands
for growth hormone secretagogues outlined in the follow-
ing papers: (a) Patchett, A. A.; Nargund, R. P.; Tata, J.
R.; Chen, M.-H.; Barakat, K. J.; Johnston, D. B. R.;
Cheng, K.; Chan, W. W.-S.; Butler, B. Proc. Natl. Acad.
Sci. U.S.A. 1995, 79, 7001; (b) Seyler, D. E.; Dodge, J. A.;
Osborne, J. J.; Cox, K. L.; Viswanath, D.; Wilmot, A. F.;
Keaton, M. J.; Heiman, M. L.; Bryant, H. U. Drug Dev.
Res. 2000, 49, 260; (c) MacAndrew, J. T.; Ellery, S. S.;
Parry, M. A.; Pan, L. C.; Black, S. C. Eur. J. Pharmacol.
2001, 432, 195.
Finally, compound 22o illustrates an important finding
of this paper. A comparison of compounds 22b and
22c with compound 22o illustrates the fact that mere
incorporation of a polar group into a privileged struc-
ture motif does not always lead to expected or enhanced
activity. Rather, the data suggest that placement and
orientation of this functionality are important aspect
to consider during the exploration and optimization of
an initial privileged structure containing hits. Once the
general location of the polar group has been identified,
there is usually some latitude with regard to functional
group identity and orientation that should allow further
refinement of either potency or overall properties of the
molecule.
Acknowledgment
8. Bondensgaard, K.; Ankersen, M.; Thogersen, H.; Hansen,
B. S.; Wulff, B. S.; Bywater, R. P. J. Med. Chem. 2004, 47,
488.
9. Brown, W. D.; Gouliaev, A-H. Synthesis 2002, 83.
10. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144.
11. Romero, A. G.; Leiby, J. A.; McCall, R. B.; Piercey, M.
F.; Smith, M. W.; Han, F. J. Med. Chem. 1993, 36, 2066.
12. Speicher, A.; Klaus, T.; Eicher, T. J. Prakt. Chem./Chem-
Ztg 1998, 340, 581.
The authors thank Mark Heiman for many helpful
discussions.
References and notes
1. Strand, F. L. Ann. N.Y. Acad. Sci. 1999, 897, 1.
2. Smith, P. E. Science 1916, 44, 280.
3. Cone, R. D.; Mounthoy, K. G.; Robbins, L. S.; Nadu, J.
H.; Johnson, K. R.; Roselli-Rehfuss, L.; Mortund, M. T.
Ann. N.Y. Acad. Sci. 1993, 680, 342.
4. For examples of efforts directed at the preparation of
selective ligands see: (a) Pan, K.; Scott, M. K.; Lee, D. H.
S.; Fitzpatrick, L. J.; Crooke, J. J.; Rivero, R. A.;
Rosenthal, D. I.; Vaidya, A. H.; Zhao, B.; Reita, A. B.
Biorg. Med. Chem. Lett. 2003, 11, 185; (b) Sebhat, I. K.;
Martin, W. J.; Ye, S.; Marakat, K.; Mosley, R. T.;
Johnston, D. B. R.; Bakshi, R.; Palucki, B.; Weinberg, D.
H.; MacNeil, T.; Kalyani, R. N.; Tang, R.; Sterns, R. A.;
Tamvakopoulos, C.; Strack, A. M.; McGowan, E.;
13. The details of the binding assay have been recently
described. See Ref. 5.
14. Functional activity was determined by measuring the
cAMP release with a standard luciferase assay employing
HEK 293 cells stably transfected with hMC4 (data not
shown). Compounds of this paper were agonists with
relative efficacies 60–100% of the maximum response
obtained with NDP-a-MSH.
15. Each data point represents the average of at least two
determinations with an average error of the binding assay
being 15%.
16. Boninell, W.E.; Neeb, M.J. WO 02/05819, 2002; Chem.
Abstr. 2002, 136, 134783.