Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1- dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl] -2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin su

Article abstract of DOI:10.1016/j.bmcl.2005.05.109

A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.

Full text of DOI:10.1016/j.bmcl.2005.05.109

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3501–3505
Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-
4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-
fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo-
[2.2.2]octane-6-carboxamide (3, RY764), a potent and
selective melanocortin subtype-4 receptor agonist
Zhixiong Ye,a,* Liangqin Guo,a Khaled J. Barakat,a Patrick G. Pollard,a
Brenda L. Palucki,a Iyassu K. Sebhat,a Raman K. Bakshi,a Rui Tang,b
Rubana N. Kalyani,b Aurawan Vongs,b Airu S. Chen,b Howard Y. Chen,b
Charles I. Rosenblum,b Tanya MacNeil,b David H. Weinberg,b Qianping Peng,c
Constantin Tamvakopoulos,c Randy R. Miller,c Ralph A. Stearns,c Doreen E. Cashen,d
William J. Martin,d Joseph M. Metzger,d Alison M. Strack,d D. Euan MacIntyre,d
Lex H. T. Van der Ploeg,b Arthur A. Patchett,a Matthew J. Wyvratta and Ravi P. Nargunda
aDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
bDepartment of Obesity Research, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
cDepartment of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
dDepartment of Pharmacology, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
Received 10 May 2005; revised 25 May 2005; accepted 26 May 2005
Abstract—A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is
reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.
Ó 2005 Elsevier Ltd. All rights reserved.
The worldwide prevalence of obesity is increasing at an
alarming rate, with major adverse consequences for
human health including increased risk for diabetes and
cardiovascular disease. The search for an effective treat-
ment for obesity is progressing on many fronts. Several
physiological systems and pathways that regulate body
weight in mammals have been identified in recent years.1
Studies suggest that the centrally located melanocortin
system may be a fundamental component in the regula-
tion of appetite, body weight, and energy homeostasis.2
All five known subtype melanocortin receptors (MC1R–
MC5R) are activated by the endogenous agonists a-, b-,
and c-melanocyte-stimulating hormones (MSHs) and
adrenocorticotropin (ACTH). These peptides are de-
rived from pro-opiomelanocortin (POMC) and they
mediate a diverse number of physiological functions
such as inflammation, skin pigmentation, steroidogene-
sis, food intake, energy expenditure, sexual behavior,
and exocrine gland secretion.3 Highly expressed in the
hypothalamus, and dorsal motor nucleus of the vagus
in the caudal brainstem, the melanocortin-4 receptor
(MC4R) has been linked to the control of feeding and
sexual behaviors. The localization of the receptor corre-
lates quite well with the brain sites displaying high sen-
sitivity to melanocortin-regulated feeding responses to
exogenously applied ligands.4 Pharmacological evidence
that modulation of melanocortin receptors might pro-
vide a mechanism for regulation of energy balance and
erectile function has come from studies using MC4R
agonist and antagonist peptides. Administration of ago-
nists to rodents decreases food consumption and
increases erectile responses, while antagonist administra-
tion produces the opposite effect suggesting that selec-
Keywords: Melanocortin; Isoquinuclidines; Food intake.
*
Corresponding author. Tel.: +1 732 594 5644; fax: +1 732 594
3007; e-mail: zhixiong_ye@merck.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.109

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Z. Ye et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3501–3505
tive MC4R agonists may prove useful for the treatment
of obesity and impotency.5
Although peptides have been used extensively to charac-
terize receptor systems, the development of peptides into
pharmaceutical products is generally limited due to poor
bioavailability. Thus, intensive efforts have gone into the
identification of MC4R selective small molecule ligands
for the treatment of obesity and sexual dysfunction.6 We
recently reported the discovery of potent and selective
MC4R agonists 1 (THIQ)6i and 2 (MB243)6a (Fig. 1).
Both compounds 1 and 2 displayed significant activities
in the control of feeding behavior and in the stimulation
of erectile response in our rodent models. However,
undesirable properties such as covalent protein-binding
activity in vitro prompted further optimization of com-
pounds in this series.7 In this study, we report the use of
isoquinuclidines, in 3 (RY764), as a replacement for the
piperazine residue of 2 to attenuate oxidative metabo-
lism and subsequent binding to liver microsomal pro-
teins. This modification enhanced in vivo efficacy of
the series. The tert-butyl amide-privileged structure (4)
and p-fluoro-(D)-phenylalanine residues were kept intact
to maintain adequate functional potency.8
Scheme 1. Reagents and conditions: (a) NaBH4, PhCH2OCOCl,
MeOH, ꢀ70 °C; (b) methyl acrylate, hydroquinone, 85 °C; (c) NaOH,
H2O–MeOH; (d) I2, KI, NaHCO3, H2O; (e) Zn, HOAc; (f) H2, Pd/C,
MeOH; (g) (Boc)2O, NaOH, dioxane; (h) (S)-4-benzyl-2-oxazolidi-
none, pivaloyl chloride, LiCl, Et3N, THF; (i) LiOH, H2O2, THF–H2O.
The synthesis of isoquinuclidines has been reported in
the literature.9 Preparation began with 1-carbobenzyl-
oxy-1,2-dihydropyridine (5), which was obtained by the
reaction of pyridine with sodium borohydride followed
by the addition of benzylchloroformate (Scheme 1).
The isoquinuclidine core was generated in a Diels–Alder
reaction between dihydropyridine 5 and methyl acrylate.
The separation of the resultant exo- and endomixture of
6 and 7 or their hydrogenated derivatives proved diffi-
cult. Hence, the mixture of 6 and 7 was hydrolyzed
and treated with iodine. This resulted in conversion of
the endoisomer into iodolactone 9. After separation,
compound 9 was incubated with zinc powder to regener-
ate the acid 10. Hydrogenation of 8 and 10 followed by
treatment with di-tert-butyl dicarbonate gave the pro-
tected isoquinuclidine acids 11 and 12, respectively. Sep-
aration of enantiomers was achieved via coupling of
compounds 11 and 12 with (S)-4-benzyl-2-oxazolidinone
to produce, after hydrolysis of the separated diastereoi-
somers, the enantiomerically pure acids 13 and 14 (syn-
isomers) and 15 and 16 (anti-isomers), respectively.10
The absolute configurations were assigned according to
literature9b and Mosher amide analysis.11
The privileged structure, N-(tert-butyl)-4-cyclohexylpi-
peridine-4-carboxamide (4), was synthesized as de-
scribed earlier.6a A sequential coupling of compound 4
with p-fluoro-(D)-phenylalanine and the isoquinuclidine
acids 13–16 in the presence of N-(3-dimethylaminopro-
pyl)-N0-ethylcarbodiimide followed by deprotection
afforded 18, 19, 20, and 21, respectively (Scheme 2).
Reductive amination of the amines 20 and 21 with form-
aldehyde furnished 22 and 3.
Binding affinities and functional activities at the human
melanocortin receptors were evaluated in competitive
binding assays using radiolabeled ligand [125I]-NDP-a-
MSH and in cAMP assays employing CHO cells
expressing the receptors.12 The in vitro data for com-
pounds 3 and 18–22 are summarized in Tables 1 and
2. Compounds 20 and 21, bearing an anti-isoquinucli-
dine, were more potent than 18 and 19, bearing a syn-
isoquinuclidine, in both binding affinity and functional
activity at the human MC4 receptor. Among the anti-
isomers, the two were equipotent in binding but
(1R,4S,6R)-isoquinuclidine analog 21 possessed a slight
edge in functional activity at the human MC4 receptor.
However, no bioavailability was observed for 21 in
pharmacokinetic studies in rats. Methylation of the iso-
quinuclidine amine of 20 and 21 afforded 22 and 3. The
latter exhibited an approximately 2-fold increase in
binding affinity and a 2-fold improvement in functional
activity at the human MC4 receptor.
Figure 1. Structures of compounds 1, 2, and 3.

Z. Ye et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3501–3505
3503
Table 3. Binding affinity and functional activity of compound 3 in
human, rat, mouse, and dog melanocortin receptorsa
Receptor Bindingb IC50 (nM) cAMPc EC50 (nM) Activationd at
[% inh.]
750 70
hMC2R >10,000
[% max]
10 lM (%)
hMC1R
160 30 [75]
2
8
1
4
hMC3R
hMC4R
hMC5R
rMC4R
mMC4R
dMC4R
942 42
8
945 44
1
11 1 [81]
850 130 [33]
3
3
7
1
1
2
5
6
1 [80]
1 [54]
11 2 [65]
a
All data represent at least three determinations.
b
Displacement of [125I]-NDP-a-MSH receptors expressed in CHO
cells. Values are represented as means standard error except for
where indicated.
c
Concentration of compound at 50% maximum cAMP accumulation.
Values are represented as means standard error except for where
indicated.
Scheme 2. Reagents and conditions: (a) N-Boc-p-fluoro-(D)-Phe,
EDC, HOBt, DIEA, CH2Cl2; (b) TFA, CH2Cl2; (c) 13–16, EDC,
HOBt, DIEA, CH2Cl2; (d) HCl, dioxane; (e) HCHO, NaBH3CN,
NaOAc, MeOH.
d
Percentage of cAMP accumulation at 10 lM compound relative to
a-MSH. Values are represented as means standard error except
for where indicated.
able melanocortin receptor subtype selectivity. It was
further evaluated in vitro on rat, mouse, and dog mela-
nocortin receptors. Data are listed in Table 3. The com-
pound showed slightly higher potency in rat and mouse
cells than in dog and human cells. On the basis of its
good potency at hMC4 receptors in all cell lines and
acceptable subtype selectivity at the human receptors,
the compound was subjected to further in vivo
characterization.
Table 1. Binding affinity of compounds at the human melanocortin
receptorsa
b
IC50 (nM)
Compounds
MC4R
MC3R
MC5R
a-MSH
3
19
8
2
1
8
8
2
6
1
19
2
118 19
945 44
942 42
1350 170
2060 320
620 160
690 240
410 120
18
19
20
21
22
28
41
14
16
6
6460 1150
9870 880
1020 290
940 150
1080 340
In pharmacokinetic studies, compound 3 displayed
moderate-to-good bioavailability (F) in rats, dogs, and
monkeys. With good plasma drug exposure and relative-
ly long duration in all species, compound 3 was chosen
as a candidate for evaluating feeding effects in animal
models (see Table 4).
a Values are represented as means standard error. All data represent
at least three determinations.
[
b Displacement of 125I]-NDP-a-MSH from the human receptors
expressed in CHO cells.
Compound 3 was evaluated for its effects on food intake
in vivo in Sprague–Dawley rats in a fasting induced
refeeding paradigm. Twelve-week-old, male, Sprague–
Dawley rats were fasted for 18 h. The compound was
orally administered in a 0.5% methylcellulose vehicle
at 2, 6, or 20 mg/kg. Food intake was measured at 2,
Table 2. Functional activity of compounds at human melanocortin
receptorsa
b
Compounds
EC50 (nM) [% max]c
MC4R
MC3R
MC5R
a-MSH
3
1.9 0.1 [100] 1.1 0.1 [102]
17 1 [113]
850 130 [33]
[14 3]
11 1 [81]
165 31 [22]
238 59 [59]
52 3 [57]
[8 4]
[5 1]
[10 3]
[3 4]
[4 3]
[4 4]
18
19
20
21
22
Table 4. Pharmacokinetic data for compound 3 in preclinical species
1980 230 [26]
[3 4]
[11 7]
PK parameter
Rata
Dogb
Monkeyc
20 5 [90]
34 10 [58]
F (%)
32
50
16
[5 5]
Cl (mL/min/kg)
Vdss (L/kg)
t1/2 (h)
46.9
9.6
3.2
3
6.6
2.3
4.9
1.1
2.7
0.91
3.4
0.8
4.6
1.3
1.3
0.85
a
Values are represented as means standard error except for where
indicated. All data represent at least three determinations.
b Concentration of compound at 50% maximum cAMP accumulation.
c
Tmax (h)
AUCnorm (lM h kg/mg)
Cmax (lM)
Percentage of cAMP accumulation at 10 lM compound relative to
0.196
0.87
a-MSH and values represent means standard deviation.
a Compound dosed in Sprague–Dawley rats as a solution in water at
1 mg/kg, iv and 20 mg/kg, po.
b Compound dosed in beagles as a solution in water at 0.5 mg/kg, iv
and 2.0 mg/kg, po.
Overall, compound 3 was the most promising com-
pound in the series. It exhibited excellent binding affinity
(IC50 of 8 nM) and agonist potency (EC50 of 11 nM with
81% activation) at the human MC4 receptor and accept-
c Compound dosed in rhesus as a solution in water at 0.5 mg/kg, iv and
2 mg/kg po.

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Z. Ye et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3501–3505
8, and 18 h postdosing. Significant food intake reduction
was observed at 8-h (ꢀ39%, P < 0.05) and 18-h (ꢀ37%,
P = 0.055) timepoints. In an overnight food intake study
in MC3/4R knockout (KO) and wild type (WT) mice,
compound 3 displayed a significant food intake reduc-
tion in WT mice (ꢀ28%, P = 0.004) but not in KO mice
(ꢀ8.6%, P = 0.19). The data suggested that the reduc-
tions of food intake observed in the rodents are a mech-
anism-based event mediated by the MC4 receptor (see
Fig. 2).
Further in vivo studies were performed to evaluate the
erectogenic activity of 3 using an established rodent
model of erectile function.3a,6j,k Compound 3 augment-
ed the magnitude and duration of electrically stimulated
erectile activity following intravenous administration
(1 mg/kg) in mice (Fig. 3). Administered at 1 mg/kg,
compound 3 significantly augmented poststimulation
AUC by 34% and 26% at 15 and 45 min, respectively.
The effects were not sustained out to 60 min. At a sub-
optimal dose (0.1 mg/kg), compound 3 failed to aug-
ment electrically evoked changes in erectile activity.
Administration of 3 did not elicit erectile activity in
the absence of electrical stimulation.
Figure 3. Proerectile effects of compound 3 in anesthetized male
C57BL/6J mice. Compound 3 (1 mg/kg, iv) was administered in a
PEG400–EtOH–water (4:1:5) vehicle in sodium pentobarbital anes-
thetized mice. Electrically evoked erectile activity was measured pre,
15, 45, and 60 min postdosage, depicted as AUC (30 s poststimulation)
and percent change from baseline. Statistical significance is defined as
*P < 0.05.
Table 5. Irreversible protein binding of [3H]-3
Liver microsomes (pmol equiv/mg protein)
300-NADPH 300 + NADPH 300 + NADPH + GSH
Rat
Human
1
2
28
26
11
17
With an eye to addressing concerns of covalent protein
binding that were raised by studies of 2,7 tritium-labeled
3 was evaluated for irreversible protein binding in vitro.
We were gratified to find that introduction of the isoqu-
inuclidine has appreciably reduced the metabolic activa-
tion potential to relatively low levels following
incubation with rat and human liver microsomes (Table
5). Irreversible protein binding was measured in vivo in
rats dosed orally at 2 and 20 mpk and the study revealed
protein binding in plasma and liver at 2, 6, and 24 h
postdose was <1 pM equiv/mg of protein.
In conclusion, a new series of potent MC4R agonists
having excellent in vitro and in vivo activities has been
developed. Replacement of a piperazine ring with an iso-
quinuclidine ring attenuated covalent protein binding to
acceptable levels. Furthermore, compound 3 (RY764) is
efficacious in lowering food intake in both rats and mice
and dose-dependently augments erectile activity in mice.
References and notes
1. (a) Kuczmarski, R. J.; Flegal, K. M.; Campbell, S. M.;
Johnson, C. L. J. Am. Med. Assoc. 1994, 272, 205; (b)
Friedman, J. M. Nature 2000, 404, 632; (c) Flier, J. S. Cell
2004, 116, 337.
2. Rosenfeld, R. D.; Zeni, L.; Welcher, A. A.; Narhi, L. O.;
Hale, C.; Marasco, J.; Delaney, J.; Gleason, T.; Philo, J.
S.; Katta, V.; Jui, J.; Baumgartner, J.; Graham, M.; Stark,
K. L.; Karbon, W. Biochemistry 1998, 37, 16041.
3. (a) Martin, W. J.; MacIntyre, D. E. Eur. Urol. 2004, 45,
706; (b) Holder, J. R.; Haskell-Luevano, C. Med. Res.
Rev. 2004, 24, 325; (c) Voisey, J.; Carroll, L.; van Daal, A.
Curr. Drug Targets 2003, 4, 586; (d) Sebhat, I.; Ye, Z.;
Bednarek, M.; Weinberg, D.; Nargund, R.; Fong, T. M.
Ann. Rep. Med. Chem. 2003, 38, 31; (e) Gantz, I.; Fong, T.
Figure 2. Effect of compound 3 on overnight food intake in (A) fasted
DIO rats and (B) knockout (KO) and wild type (WT) mice. (A)
Sprague–Dawley rats were fasted overnight and then refed at the time
of dosing. Compound 3 was administered in a 0.5% methylcellulose
oral vehicle. Feeding was measured at 2, 8, and 18 h postdosing.
*P < 0.05, #P = 0.055. (B) Effect of compound 3 on overnight food
intake in KO and WT mice. Compound 3 was administered in a 0.5%
methylcellulose oral vehicle at 20 mpk to MC3/4 KO and WT mice.
Feeding was measured at 18 h postdosing. *P < 0.05.

Z. Ye et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3501–3505
3505
M. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E468; (f)
Zimanyi, I. A.; Pelleymounter, M. A. Curr. Pharm. Des.
2003, 9, 627; (g) Yang, Y. K.; Harmon, C. M. Obes. Rev.
2003, 4, 239.
Molinoff, P. B. Int. J. Impot. Res. 2004, 16, 51; (f) Dyck, B.;
Parker, J.; Phillips, T.; Carter, L.; Murphy, B.; Summers,
R.; Hermann, J.; Baker, T.; Cismowski, M.; Saunders, J.;
Goodfellow, V. Bioorg. Med. Chem. Lett. 2003, 13, 3793;
(g) Ruel, R.; Herpin, T. F.; Iben, L.; Luo, G.; Martel, A.;
Mason, H.; Mattson, G.; Poirier, B.; Ruediger, E. H.; Shi,
D.; Thibault, C.; Yu, G.; Zimanyi, I. A.; Poindexter, G. S.;
Macor, J. E. Bioorg. Med. Chem. Lett. 2003, 13, 4341; (h)
Ujjainwalla, F.; Warner, D.; Walsh, T. F.; Wyvratt, M. J.;
Zhou, C.; Yang, L.; Kalyani, R. N.; MacNeil, T.; Van der
Ploeg, L. H. T.; Rosenblum, C. I.; Tang, R.; Vongs, A.;
Weinberg, D. H.; Goulet, M. T. Bioorg. Med. Chem. Lett.
2003, 13, 4431; (i) Sebhat, I. K.; Martin, W. J.; Ye, Z.;
Barakat, K.; Mosley, R. T.; Johnston, D. B. R.; Bakshi, R.;
Palucki, B.; Weinberg, D. H.; MacNeil, T.; Kalyani, R. N.;
Tang, R.; Stearns, R. A.; Miller, R. R.; Tamvakopoulos,
C.; Strack, A. M.; McGowan, E.; 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; (j) Van der Ploeg, L. H. T.; Martin,
W. J.; Howard, A. D.; Nargund, R. P.; Austin, C. P.; Guan,
X.; Drisko, J.; Cashen, D.; Sebhat, I.; Patchett, A. A.;
Figueroa, D. J.; DiLella, A. G.; Connolly, D. H.; Wein-
berg, D. H.; Tan, C. T.; Palyha, O. C.; Pong, S.; MacNeil,
T.; Rosenblum, C.; Vongs, A.; Tang, R.; Yu, H.; Sailer, A.
W.; Fong, T. M.; Huang, C.; Tota, M.; Chang, R. S.;
Stearns, R.; Tamvakopoulos, C.; Christ, G.; Drazen, D. L.;
Spar, B. D.; Nelson, R. J.; MacIntyre, D. E. Proc. Natl.
Acad. Sci. USA 2002, 99, 11381; (k) Cashen, D. E.;
MacIntyre, D. E.; Martin, W. J. Br. J. Pharmacol. 2002,
136.
4. (a) Saper, C. B.; Chou, T.; Elmquist, T. J. Neuron 2002, 36,
199; (b) Williams, D. L.; Kaplan, J. M.; Grill, H. J.
Endocrinology 2000, 141, 1332; (c) Bagnol, D.; Lu, X-Y.;
Kaelin, C. B.; Day, H. E.; Ollmann, M.; Gantz, I.; Akil, H.;
Barsh, G. S.; Watson, S. J. J. Neurosci. 1999, 19, RC26; (d)
Mountjoy, K. G.; Mortrud, M. T.; Low, M. J.; Simerly, R.
B.; Cone, R. D. Mol. Endocrinol. 1994, 8, 1298.
5. (a) Lubrano-Berthelier, C.; Le Stunff, C.; Bougneres, P.;
Vaisse, C. J. Clin. Endocrinol. Metab. 2004, 89, 2028; (b)
Rosen, R. C.; Diamond, L. E.; Earle, D. C.; Shadiack, A.
M.; Molinoff, P. B. Int. J. Impot. Res. 2004, 16, 135; (c)
Diamond, L. E.; Earle, D. C.; Rosen, R. C.; Willett, M. S.;
Molinoff, P. B. Int. J. Impot. Res. 2004, 16, 135; (d)
Wessells, H.; Hruby, V. J.; Hackett, J.; Han, G.; Balse-
Srinivasan, P.; Vanderah, T. W. Neuroscience 2003, 118,
755; (e) Lubrano-Berthelier, C.; Cavazos, M.; Le Stunff,
C.; Haas, K.; Shapiro, S.; Zhang, S.; Bougneres, P.;
Vaisse, C. Diabetes 2003, 52, 2996; (f) Illum, L. Drug
Discovery Today 2002, 7, 1184; (g) Fehm, H. L.; Smolnik,
R.; Kern, W.; McGregor, G. P.; Bickel, U.; Born, J. J.
Clin. Endocrinol. Metab. 2001, 86, 1144; (h) Obici, S.;
Feng, Z.; Tan, J.; Liu, L.; Karkanias, G.; Rossetti, L. J.
Clin. Invest. 2001, 108, 1079; (i) Chen, A. S.; Metzger, J.
M.; Trumbauer, M. E.; Guan, X.-M.; Yu, H.; Frazier, E.
G.; Marsh, D. J.; Forrest, M. J.; Gopal-Truter, S.; Fisher,
J.; Camacho, R. E.; Strack, A. M.; Mellin, T. N.;
MacIntyre, D. E.; Chen, H. Y.; Van der Ploeg, L. H. T.
Transgenic Res. 2000, 9, 145; (j) Farooqi, I. S.; Yeo, G. S.;
Keogh, J. M.; Aminian, S.; Jebb, S. A.; Butler, G.;
Cheetham, T.; OÕRahilly, S. J. Clin. Invest. 2000, 106, 271;
(k) Fan, W.; Dinulescu, D. M.; Butler, A. A.; Zhou, J.;
Marks, D. L.; Cone, R. D. Endocrinology 2000, 141, 3072;
(l) Gu, W.; Tu, Z.; Kleyn, P. W.; Kissebath, A.; Duprat,
L.; Lee, J.; Chin, W.; Maruti, S.; Deng, N.; Fisher, S. L.;
Franco, L. S.; Burn, P.; Yagaloff, K. A.; Nathan, J.;
Heymsfield, S.; Albu, J.; Pi-Sunyer, F. X.; Allison, D. B.
Diabetes 1999, 48, 635; (m) Huszar, D.; Lynch, C. A.;
Fair-Huntress, V.; Dunmore, J. H.; Fang, Q.; Berkemeier,
L. R.; Gu, W.; Kesterson, R. A.; Boston, B. A.; Cone, R.
D.; Smith, F. J.; Campfield, L. A.; Burn, P.; Lee, F. Cell
1997, 88, 131; (n) Fan, W.; Boston, B. A.; Kesterson, R.
A.; Hruby, V. J.; Cone, R. D. Nature 1997, 385, 165; (o)
Lu, D.; Willard, D.; Patel, I. R.; Kandell, S.; Overton, L.;
Kost, T.; Luther, M.; Chen, W.; Woychik, R. P.;
Wilkison, W. O.; Cone, R. Nature 1994, 371, 799.
6. (a) Palucki, B. L.; Park, M. K.; Nargund, R. P.; Ye, Z.;
Sebhat, I. K.; Pollard, P. G.; Kalyani, R. N.; Tang, R.;
MacNeil, T.; Weinberg, D. H.; Vongs, A.; Rosenblum, C.
I.; Doss, G. A.; Miller, R. R.; Stearns, R. A.; Peng, Q.;
Tamvakopoulos, C.; McGowan, E.; Martin, W. J.; Metz-
ger, J. M.; Shepherd, C. A.; Strack, A. M.; MacIntyre, D.
E.; Van der Ploeg, L. H. T.; Patchett, A. A. Bioorg. Med.
Chem. Lett. 2005, 15, 171; (b) 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.;
Herr, R. J.; Melekhov, A.; Sampson, P. B.; King, C.-H. R.
J. Med. Chem. 2004, 47, 744; (c) Xi, N.; Hale, C.; Kelly, M.
G.; Norman, M. H.; Stec, M.; Xu, S.; Baumgartner, J. W.;
Fotsch, C. Bioorg. Med. Chem. Lett. 2004, 14, 377; (d)
Rosen, R. C.; Diamond, L. E.; Earle, D. C.; Shadiack, A.
M.; Molinoff, P. B. Int. J. Impot. Res. 2004, 16, 1; (e)
Diamond, L. E.; Earle, D. C.; Rosen, R. C.; Willett, M. S.;
7. Doss, G. A.; Miller, R. R.; Zhang, Z.; Teffera, Y.;
Nargund, R. P.; Palucki, B.; Park, M. K.; Tang, Y. S.;
Evans, D. C.; Baillie, T. A.; Stearns, R. A. Chem. Res.
Toxicol. 2005, 18, 271.
8. (a) Bakshi, R. K.; Hong, Q.; Olson, J. T.; Ye, Z.; Sebhat, I.
K.; Barakat, K.; Pollard, P. G.; Weinberg, D. H.;
MacNeil, T.; Kalyani, R. N.; Tank, R.; Martin, W. J.;
Strack, A.; Cashen, D. E.; Drisko, J. E.; Horn, G. J.;
Howard, A. D.; Tamvakopoulos, C.; Miller, R. R.;
Stearns, R. A.; MacIntyre, D. E.; Van der Ploeg, L. H.
T.; Patchett, A. A.; Nargund, R. P. Abstracts of Papers,
225th National Meeting of the American Chemical Soci-
ety, New Orleans, LA, 2003; Abstract MEDI-005; (b) Ye,
Z. et al. Unpublished results.
9. (a) Santos, D. C.; Freitas-Gil, R. P.; Gel, L.; Marazano, C.
Tetrahedron Lett. 2001, 42, 6109; (b) Mehmandoust, M.;
Marazano, C.; Singh, R.; Gillet, B.; Cesario, M.; Fourrey,
J.-L.; Das, B. C. Tetrahedron Lett. 1988, 29, 4423; (c)
Morelli, J. F.; Pouilhes, A.; Langlois, Y. Tetrahedron 1997,
53, 5195; (d) Campbell, M. M.; Mahon, M. F.; Sainsbury,
M.; Searle, P. A.; Davies, G. M. Tetrahedron 1992, 48, 8751;
(e) Street, L. J.; Baker, R.; Book, R.; Kneen, C. O.;
MacLeod, A. M.; Merchant, K. J.; Showell, G. A.;
Saunders, J.; Herbert, R. H.; Freedman, S. B.; Harley, E.
A. J. Med. Chem. 1990, 33, 2690; (f) Kouklovsky, C.;
Pouilhes, A.; Langlois, Y. J. Am. Chem. Soc. 1990, 112,
6672.
10. syn-Isomer is defined by the functional groups on the same
side of the molecule and the anti-isomer has the functional
groups on opposite side of the molecule.
11. (a) Hoye, T. R.; Renner, M. K. J. Org. Chem. 1996, 61,
8489; (b) Hoye, T. R.; Renner, M. K. J. Org. Chem. 1996,
61, 2056.
12. (a) Bednarek, M. A.; MacNeil, T.; Kalyani, R. N.; Tang,
R.; Van der Ploeg, L. H. T.; Weinberg, D. H. J. Med.
Chem. 2001, 44, 3665; (b) Bednarek, M. A.; Siva, M. V.;
Arison, B.; MacNeil, T.; Kalyani, R. N.; Huang, R.-R. C.;
Weinberg, D. H. Peptides 1999, 20, 401.