Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1- (4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl) piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist

Article abstract of DOI:10.1021/jm025539h

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.

Full text of DOI:10.1021/jm025539h

© Copyright 2002 by the American Chemical Society
Volume 45, Number 21
October 10, 2002
Letters
Design a n d P h a r m a cology of
N-[(3R)-1,2,3,4-Tetr a h yd r oisoqu in olin iu m -
3-ylca r bon yl]-(1R)-1-(4-ch lor oben zyl)-
2-[4-cycloh exyl-4-(1H-1,2,4-tr ia zol-
1-ylm eth yl)p ip er id in -1-yl]-2-oxoeth yla m in e
(1), a P oten t, Selective, Mela n ocor tin
Su btyp e-4 Recep tor Agon ist
Iyassu K. Sebhat,*,† William J . Martin,‡ Zhixiong Ye,†
Khaled Barakat,† Ralph T. Mosley,†
F igu r e 1. Synthetic ligands MT-II and 1.
David B. R. J ohnston,† Raman Bakshi,†
Brenda Palucki,† David H. Weinberg,§
Tanya MacNeil,§ Rubana N. Kalyani,§ Rui Tang,§
Ralph A. Stearns,| Randy R. Miller,|
endogenous ligands (the corticotropins and melanocort-
ins) to mediate a wide array of activities, from the
control of feeding and sexual behavior to skin pigmenta-
tion and neuroendocrine regulation. The melanocortin
subtype-4 receptor (MC4R) is expressed in various
regions of the brain,1 and evidence pointing to the role
of this receptor in feeding behavior has been summar-
ized.2-10 This includes obesity observed in animals that
overexpress the coat-color regulating protein agouti, a
competitive MC4R and MC1R antagonist.3,4 It was later
discovered that injection of MC4R agonists into the
brain inhibits food intake in rodents.5-8 There is a
converse increase following intracerebroventricular ad-
ministration of antagonists.8-10 This link between MC4R
and feeding regulation was strengthened by gene-
deletion studies of the receptor resulting in obese mice.11
Thus, agonism at MC4R produces a lean phenotype
while inhibition or inactivation of the receptor results
in obesity. These findings have led to intense efforts to
identify suitable agonists of the receptor as possible
treatments for obesity.
Central administration of the endogenous melano-
cortin receptor agonists ACTH and R-MSH has been
shown to elicit erectile activity in rodents.2,12 More
recently, melanotan-II (MT-II, Figure 1), a potent ago-
nist with subnanomolar EC50 values at MC1R, MC3R,
MC4R, and MC5R, was developed.13 Wessells and co-
workers reported erectile activity on administration of
the synthetic peptide to human subjects. Subcutaneous
doses resulted in a significant onset of transient erec-
tions in 8 out of 10 men with psychogenic erectile
Constantin Tamvakopoulos,† Alison M. Strack,‡
Erin McGowan,‡ Doreen E. Cashen,‡
J ennifer E. Drisko,‡ Gary J . Hom,‡
Andrew D. Howard,§ D. Euan MacIntyre,‡
Lex H. T. van der Ploeg,§ Arthur A. Patchett,† and
Ravi P. Nargund†
Departments of Chemistry, Pharmacology, Obesity Research,
and Drug Metabolism, Merck & Co., Inc., P.O. Box 2000,
Rahway, New J ersey 07065-0900
Received May 14, 2002
Abstr a ct: Synthetic and natural peptides that act as nonse-
lective melanocortin receptor agonists have been found to be
anorexigenic and to stimulate erectile activity. We report the
design and development of 1, a potent, selective (1184-fold vs
MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4
receptor. Pharmacological testing confirms the food intake
lowering effects of MC4R agonism and suggests another role
for the receptor in the stimulation of erectile activity.
In tr od u ction . The melanocortin receptors are a
family of seven-transmembrane G-protein-coupled re-
ceptors. The five known subtypes interact with their
* To whom correspondence should be addressed. Phone: (732) 594
0168. Fax: (732) 594 3007. E-mail: iyassu_sebhat@merck.com.
† Department of Chemistry.
‡ Department of Pharmacology.
§ Department of Obesity Research.
| Department of Drug Metabolism.
10.1021/jm025539h CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/14/2002

4590 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21
Letters
Sch em e 1. Synthesis of 1 and Its Stereoisomersa
F igu r e 2. Endogenous ligand R-MSH, synthetic cyclic ligands
MT-II and SHU-9119, and the growth hormone secretagogue
peptide GHRP-6.
a
Reagents: (a) SOCl2/EtOH; (b) (i) LAH/THF, (ii) Rh/Al2O3/
H2/HCl/MeOH, (iii) Boc2O/Et3N/MeOH; (c) (i) MsCl/Et3N/CH2Cl2,
(ii) Na-triazole/DMF; (d) HCl/CH2Cl2; (e) Boc-(L or D)-Phe(pCl)-
OH/EDC/HOBt/NMM/CH2Cl2; (f) Boc-(L or D)-Tic-OH/EDC/HOBt/
NMM/CH2Cl2.
Merck sample collection found 3 containing the piperi-
dine coupled to naphthylalanine and His, closely re-
sembling the antagonist SHU-9119. Compound 3 was
found to have a binding IC50 of 108 nM at MC4R,
inducing little or no activation. Modification of the
phenylalanine residue in the cyclic peptides exerts a
large influence on agonist activity.18 Similarly, a change
from naphthylalanine to phenylalanine provided our
first agonist lead: 4 (EC50 ) 500 nM; 97% activation).
Optimization led to a series of 4-substituted 4-cyclo-
hexylpiperidine-based structures. A very potent class
emerged where the piperidine is substituted with a
methylene bearing a heterocycle. Replacement of His
with 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid
(Tic) further enhanced potency and selectivity.
F igu r e 3. Lead discovery and optimization.
dysfuntion14 and in 9 out of 10 of those studied with
organic dysfunction.15
Ch em istr y. The synthesis of the compounds required
one of two routes. These are outlined in Schemes 1 and
2.
To determine which receptor subtype mediates these
observed erectogenic effects, more selective agonists
were sought. We report here the design of a highly
potent MC4R selective agonist, 1, and its activity in
studies to assess food intake and erectile activity.
Design Con sid er a tion s. Both ACTH and the MSH
peptides contain a common His-Phe-Arg-Trp core unit
(Figure 2) essential for their functional activities (EC50).
Structure-activity studies about this core have gener-
ated various truncated, cyclic analogues including the
heptapeptides MT-II and SHU-9119.13,16-18
The synthesis of the triazole-based compounds began
with the core skeleton in place. N-Boc-4-phenylpiperi-
dine-4-carboxylic acid was initially esterified. The amino
ester 8 was then reduced with LiAlH4, the aromatic ring
saturated, and the amine protected to generate 9.
Substitution gave triazole 10, which was deprotected
and coupled to L- and D-Phe(pCl) and then to L- and
D-Tic to give, after a final deprotection, 1 and its
stereoisomers 13, 14, and 15.
There is close homology between the common phar-
macophore and the active core of the growth hormone
secretagogue peptide GHRP-6.19 A clinical candidate, 2
(Figure 3), had been developed in a growth hormone
project at Merck. Modeling and molecular calculation
suggested that the spiroindanyl piperidine functions
as an Ala-Trp mimetic.20
The synthesis of the tetrazoles required construction
of the core skeleton and proceeded initially with the
Knoevenalgel condensation of Cbz-protected 4-piperi-
done with ethyl cyanoacetate. The resultant unsatur-
ated cyanoacetate 16 was treated with a cuprate gen-
erated from cyclohexylmagnesium chloride. The 4-cyclo-
hexylpiperidine was then thermally decarboxylated to
generate nitrile 17. Cycloaddition of azide afforded the
free tetrazole, which was deprotected and coupled to the
We anticipated that such an approach would extend
to the design of an MC4R lead. A directed search of the

Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4591
Sch em e 2. Synthesis of Tetrazole Compounds 5-7a
Ta ble 2. Functional Activity of Compounds at Human
Melanocortin Receptorsa
b
EC50 (nM) [% max]c
compd
MC4R
MC3R
MC5R
1
13
14
15
5
2.1 ( 0.24 [97]
8.7 ( 4 [67]
[9]
2487 ( 43 [32]
736 ( 65 [61]
271 ( 7 [19]
[2]
[5]
[15]
127 ( 6 [51]
1004 ( 46 [38]
[7]
[1]
[4]
[34]
771 ( 32 [79]
0.6 ( 0.2[103]
9.6 ( 1.5 [87]
[10]
59 ( 1 [50]
[24]
6
7
a
b
Values (n ) 2) with standard errors. Concentration of
compound at 50% maximum cAMP accumulation. c Percentage of
cAMP accumulation at 10 µM compound relative to R-MSH.
Ta ble 3. Binding Affinity and Functional Activity of 1 at
Human and Rat Melanocortin Receptors
bindinga
cAMPb
activationc
receptor
IC50 (nM)
EC50 (nM)
at 10 µM (%)
hMC1R
hMC3R
hMC4R
hMC5R
rMC3R
rMC4R
rMC5R
2067 ( 73
761 ( 31
1.2 ( 0.11
326 ( 9
1883 ( 478
0.6 ( 0.16
1575 ( 372
2850 ( 450
2487 ( 43
2.1 ( 0.2
737 ( 65
1325 ( 607
2.9 ( 0.8
>3000
95
32
97
61
65
99
58
a
Reagents: (a) NH4Cl/AcOH/C6H6; (b) (i) cyclohexylmagnesium
a
Displacement of [125I]-NDP-R-MSH from receptors expressed
chloride/CuCN/THF, (ii) LiCl/H2O/DMSO; (c) TMSN3/Bu2SnO/
toluene; (d) (i) Pd(OH)2/H2/HCl/MeOH, (ii) Boc-D-Phe(pCl)-OH/
EDC/HOBt/NMM/CH2Cl2; (e) HCl/CH2Cl2; (f) Boc-D-Tic-OH/EDC/
HOBt/NMM/CH2Cl2; (g) K2CO3/MeI/DMF.
b
in CHO cells (n > 15). Concentration of compound at 50%
maximum cAMP accumulation (n > 5). c Percentage of cAMP
accumulation at 10 µM relative to R-MSH.
Ta ble 4. Pharmacokinetic Data for 1
Ta ble 1. Binding Affinity and Selectivity of Compounds for the
Human Melanocortin 4 Receptora
PK parameter
F (%)
Cl (mL min-1 kg-1
Vdss (L kg-1
1/2 (h)
Tmax (h)
rata
dogb
b
IC50 (nM)
14
16
)
84 ( 2
27.55 ( 0.2
2.79 ( 0.02
1.2 ( 0.1
compd
MC4R
MC3R/4R
MC5R/4R
)
3.6 ( 0.2
0.6 ( 0.05
1 ( 0.05
1
13
14
15
5
1.2 ( 0.11
0.5 ( 0.14
3050 ( 150
127 ( 32
634
336
0.3
57
53
277
601
272
130
1.3
9.4
19
t
1.5 ( 0.5
a
Compound dosed in Sprague-Dawley rats as a solution in
EtOH/PEG/saline (1:4:5) at 1 mg/kg, iv (n ) 2) and 10 mg/kg, po
238 ( 26
b
(n ) 2). Compound dosed in beagles as a solution in EtOH/PEG/
6
7
0.3 ( 0.09
1.2 ( 0.15
100
258
saline (1:4:5) at 0.2 mg/kg, iv (n ) 2) and 0.5 mg/kg, po (n ) 2).
a
b
Values (n ) 2) with standard errors. Displacement of [125I]-
acidity in the region. The two methylated compounds 6
and 7 show very high potency with strong activation of
the receptor. While the 1-methyltetrazole 6 is the most
potent compound in the series, its reduced selectivity
makes it less attractive than triazole 1. Data for this
compound are outlined in more detail in Table 3. 1 is
over 100-fold selective vs the other human receptor
subtypes. It is a full agonist at MC1R (binding only
weakly to the receptor) and at MC4R. Selectivity is
better still at the rat receptors.
The compound was characterized in pharmacokinetic
(PK) studies (Table 4). Bioavailability was moderate for
the rat and dog. The compound is rapidly absorbed
(short Tmax), but relatively fast plasma clearance results
in short duration in both species (t1/2(rat) ) 30 min).
Figure 4 shows the superposition of a low-energy
conformer of 1 onto a low-energy conformation of MT-
II. The residues common to MT-II and R-MSH (in
purple) were used as a probe over multiple energy-
minimized conformations of 1 using SQ22 to identify the
energetically most stable conformer.
NDP-R-MSH from human receptors expressed in CHO cells.
dipeptide cap. Methylation prior to final deprotection
gave the 1- and 2-methyltetrazoles 6 and 7.
Resu lts a n d Discu ssion
The compounds were evaluated in two primary as-
says: affinity to the melanocortin subtypes was assessed
in a competitive binding assay (Table 1); agonist potency
was determined in cAMP release assays using CHO
cells expressing the relevant receptors (Table 2).21 The
compounds bearing S (or L) stereochemistry at the Phe-
(pCl) residue (14 and 15) bind poorly at MC4R. cAMP
levels generated in functional assays suggest that the
compounds are at best only partial agonists (9-34%).
Conversely the 1R (or D) isomers 1 and 13 show high
affinity for the receptor and activation at a concentra-
tion of 10 µM approaching that of R-MSH. The 3R (D-
Tic) isomer 1 exhibits marginally higher IC50 but
improved functional activity.
Compound 1 was evaluated for its effects on food
intake. In line with the observed effects of other MC4R
agonists, food intake was significantly reduced on
administration of the compound.23
The tetrazoles were synthesized bearing the optimized
1R,3R stereochemistry. The parent compound 5 shows
poor potency, suggesting that binding is disrupted by

4592 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21
Letters
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10 (n ) 6) mg/kg produced comparable increases. (///) p <
0.001, compared to vehicle treatment (paired t test).
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lished rodent model24-26 such that each rat served as
its own control. The mean number of erections elicited
over a 15 min period (direct visual count) in vehicle-
treated rats was 27.07 ( 1.2, n ) 64. Apomorphine, a
known erectile stimulant,24 was used as a positive
control. At 0.01 mg/kg, sc, apomorphine increased penile
erections by 37% (p < 0.001; n ) 20). Higher doses
(0.05-0.1 mg/kg, sc) did not further increase erectile
responses. Following iv administration, 1 dose-depen-
dently (0.3-10 mg/kg) increased erections (ED50 ) 0.87
mg/kg; Figure 5). The maximal increase in the number
of erections (60%) was detected at 5 mg/kg but was not
significantly different from that produced by 1 mg/kg.
Following oral administration, 1 (20 mg/kg, po) also
produced statistically significant increases in erectile
responses with a mean increase of 31 ( 4% (p < 0.001;
n ) 6).25
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of a New Class of Superpotent Cyclic R-Melanotropins Based
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Phe7,Lys10] R-Melanocyte-Stimulating-(4-10)-NH2 with Bulky
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Con clu sion . Compound 1 is the first selective small-
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molar potency to be disclosed in the literature. In vivo
testing of 1 suggests that MC4R agonism plays a role
in eliciting erectile activity in rodents. While we cannot
exclude the possibility of MC3R participation, 1 main-
tains low potency at the rodent MC3 receptor. Addition-
ally, augmentation of erectile activity observed in wild-
type mice is absent in MC4R null mice.26
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Falguni Patel and Mark Levorse for assistance.

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J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 21 4593
(24) Sachs, B. D. Contextual approaches to the physiology and
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arousal. Neurosci. Biobehav. Rev. 2000, 24, 541-560.
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J M025539H