Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.08.094

To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC ₅₀ value of 3 nM with 450-fold selectivity against Orexin-1 Receptor (OX1R).

Full text of DOI:10.1016/j.bmcl.2011.08.094

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6409–6413
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of spiropiperidine-based potent and selective Orexin-2
receptor antagonists
Tatsuhiko Fujimoto a, , Yoshihide Tomata a, Jun Kunitomo a, Mariko Hirozane b, Shogo Marui a
⇑
a Medicinal Chemistry Research Laboratories,Takeda Pharmaceutical Company, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-1238, Japan
b Discovery Research Laboratories, Takeda Pharmaceutical Company, 26-1, Muraokahigashi 2-Chome, Fujisawa, Kanagawa 251-1238, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 30 August 2011
To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was
designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity
with an IC50 value of 3 nM with 450-fold selectivity against Orexin-1 Receptor (OX1R).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sleep disorder
Insomnia
Orexin-2 receptor antagonists
Spiropiperidine
MeO
O
The neuropeptides orexin-A and orexin-B are derived via prote-
olytic cleavage from a common precursor in hypothalamic neu-
rons. These endogenous ligands bind two G protein–coupled
receptors (GPCR) termed orexin receptors type 1 and type 2
(OX1R and OX2R).1 OX1R is selective for orexin-A, whereas OX2R
is a nonselective receptor for both orexin-A and orexin-B.1 Ana-
tomical studies have demonstrated that orexin neuronal projec-
tions reach throughout brain,2–4 with dense concentration of
orexin containing axon terminals in the brainstem, hypothalamus,
and basal forebrain. In particular, OX1R mRNA is the most abun-
dant in the locus coeruleus and OX2R mRNA in the tuberomamil-
lary nucleus, whereas the dorsal raphe nucleus and the ventral
tegmental area contain both OX1R and OX2R mRNA.5 These re-
gions are known to participate in the control of behavioral sleep
and wakefulness. Activation of orexin neurons contributes to the
promotion and maintenance of wakefulness, and conversely, rela-
tive inactivity of orexin neurons allows the onset of sleep.6 Conse-
quently, blocking orexin signaling with receptor antagonists
should provide a mechanism for decreasing wakefulness and, thus,
a novel therapeutic opportunity for the treatment of insomnia. In
addition, orexin R antagonist might be expected to have other ther-
apeutic potentials such as treatment of eating disorder,7 Alzhei-
mer’s disease by reducing amyloid-b,8 cognitive enhancer,9
PTSD,10 panic anxiety,11 and addiction.12
Me
N
MeO
NHMe
O
N
N
N
N
N
Cl
N
O
Me
CF3
Almorexant
MK-4305
Figure 1. Almorexant and MK-4305
however, Almorexant was discontinued (Fig. 1).14 Actelion has also
reported that the Almorexant elicited somnolence without induc-
ing cataplexy in rats, dogs, and humans,14 and demonstrated supe-
rior efficacy in subjective and objective electrophysiological signs
for treating insomnia compared to the currently available medica-
tions (e.g., GABA agonists).14 In spite of fascinating profile of the
dual orexin receptor antagonists, the intrinsic contributions of
OX1R and OX2R in sleep regulation remain to be determined using
pharmacological tools. Johnson & Johnson has reported that block-
ade of OX1R attenuates OX2R antagonist-induced sleep promotion
in the rat.15 Considering these results, our goal was to discover po-
tent, selective OX2R antagonists for clinical development and their
elucidation of pharmacological action.
Whilst numerous kinds of orexin receptor antagonists have
been reported,13 only two dual OX1R/OX2R receptor antagonists
such as Almorexant and MK-4305 were entered in Phase-III,
Among various scaffolds of orexin receptor antagonists,13 we
regarded spiropiperidine 1 disclosed by a Merck research group
as a promising CNS drug-like template because of low molecular
weight (408.52), low PSA (74.8), moderate lipophilicity (c log P:
3.64), and only two rotatable bonds typical of a rigid structure
⇑
Corresponding author.
E-mail address: Fujimoto_Tatsuhiko@takeda.co.jp (T. Fujimoto).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.094

6410
T. Fujimoto et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6409–6413
O
S
O
gave a spiropiperidine 11 and subsequent acylation afforded the
desired compound 3 (Scheme 2).
N
N
O
S
O
2: R =
3: R =
To measure potency, we utilized a FLIPR (Fluorometric Imaging
Plate Reader) assay in which calcium flux is measured as a func-
tional determinant of OX2 or OX1 antagonism. Spiropiperidine 2
showed acceptable OX2R antagonistic activity of 230 nM with sev-
enfold selectivity against OX1R, but the human metabolic stability
(HLM) was poor (Table 1).18 Phenyl urea 3 showed threefold de-
crease in potency compared with 2, however, the selectivity
against OX1R was slightly improved (8.9-fold). Additionally meta-
bolic stability in human liver microsome was improved (Table 1).
This improvement may be partially due to reduced lipophilicity
(log D: 1.82 for 3 vs 3.07 for 2).19
N
N
O
N
O
N
R
N
NH
N
1
(disclosed by Merck)
Figure 2. Spiropiperidine Compounds 2 and 3.
Both compounds 2 and 3 were evaluated by drug-like parame-
ters such as ligand efficiency (LE), ligand-lipophilicity efficiency
(LLE), and LELP.20–23 LE of both compounds are comparable. How-
ever, LLE of 3 is better than that of 2 even though the potency of 3
was weaker. It was suggested that LELP is a more useful metric par-
ticularly in CNS drug and the value below 10 is recommended as
acceptable to ensure maximum binding efficiency for molecular
size and lipophilicity.17d LELP values for compounds 2 and 3 are
9.90, and 6.07, respectively. Judging from its acceptable profile of
drug-like parameters and selectivity against OX1R, we selected 3
as a lead compound for further modification.
Although compound 3 showed 8.9-fold selectivity against
OX1R, this compound was not stable under acidic conditions prob-
ably due to the aminal substructure. Additionally, the solubility of
compound 3 was rather poor. In order to overcome those prob-
lems, we introduced a fluorine atom at the beta-position of the
piperidine nitrogen, with the expectation that the strong electro-
negativity of fluorine would enhance the stability of oxazolidine
in acidic conditions, and the collapse of the symmetrical structures
would break the crystal packing and achieve better solubility.24
Monofluorinated analogues were prepared as shown below
(Scheme 3). Formation of silyl enol ether, followed by fluorination
(Fig. 2).16,17 Inspired by this novel structure, we decided to modify
the core of 1 to identify new chemical entities endowed with po-
tency and selectivity against OX1R. In this article, we described
scaffold morphing of compound 1 that led to a novel selective
OX2R antagonist.
During the course of exploring a novel scaffold, we attempted to
introduce an oxygen atom in the spiro-ring and truncation of pyr-
azine ring, to reduce lipophilicity. The designed compounds 2 and
3 were prepared according to Scheme 1 and 2. The synthesis of
oxo-analogue 2 was achieved by four steps, namely SNAr reaction,
acetal deprotection, spiroketalization with 2-aminoethanol, and
sulfonamidation. The yield of final spiroketalization and sulfon-
amide formation steps was relatively moderate as 20% because of
low solubility of ketone 6. In the case of the synthesis of following
compound 3, the yield of ketalization step was increased because
these steps were undergone with soluble material 8 (Scheme 2).
The synthesis of 3 began with spiroketalization of Cbz-pro-
tected piperidinone 8 with 2-aminoethanol giving intermediate
9, which was directly sulfonamidated without purification to af-
ford spiropiperidine 10. Removal of Cbz group by hydrogenation
O
S
O
O
O
O
N
N
NH
N
O
N
O
N
N
N
b
c
a
d
N
N
N
N
N
Cl
N
N
N
4
5
6
7
2
Scheme 1. Synthesis of oxo-analogue 2. Reagents and conditions: (a) 1,4-dioxa-8-azaspiro[4.5]decane, NEt3, EtOH, rt, 4 h, 87%; (b) p-TSA, acetone–water reflux, overnight,
12%; (c) 2-aminoethanol, toluene, p-TSA, reflux, 5 h; (d) PhSOCl2,pyridine, rt, overnight, 20% over two steps.
O
S
O
O
S
O
O
N
NH
O
N
N
O
O
O
O
O
O
O
S
O
N
O
d
b
c
a
N
N
N
O
O
O
N
H
NH
11
9
10
3
8
Scheme 2. Synthesis of phenyl urea 3. Reagents and conditions: (a) 2-aminoethanol, toluene, p-TSA, reflux; (b) PhSO2Cl,pyridine, rt, 92% over two steps for 11; (c) 10% Pd/C,
THF–water, rt, under H2, quant.; d) PhNCO, NEt3, THF, rt, 43%.

T. Fujimoto et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6409–6413
6411
Table 1
OX2R/1R Antagonistic Activities, Selectivity Against OX1R, Human Metabolic Stabilities, LE, LLE, and LELP.
N
O
2: R =
3: R =
N
S
O
O
N
O
N
R
NH
HLMb (mL/min/mg)
cmpd
OX-2a IC50 (nM)
OX-1a IC50 (nM)
Selectivity (OX-1/OX-2)
LE
LLE
LELP
2
3
230
710
1600
6300
7.0
8.9
100
43
0.31
0.30
3.56
4.33
9.90
6.07
a
Antagonistic activity.
HLM = metabolic stability by the incubation with human liver microsomes.
b
O
S
O
O
S
O
SiMe3
O
N
O
N
N
O
N
N
O
O
O
O
F
F
F
N
a
N
b
c- f
+
NH
O
O
O
O
NH
O
O
4a
4b
8
13
12
Scheme 3. Synthesis of Monofluorinated Compounds 4a and 4b. Reagents and conditions: (a) TMSCl, NEt3, DMF, 80 °C, overnight, 48%; (b) Selectfluor, MeCN, rt, 2 h, 67%; (c)
2-aminoethanol, toluene, p-TSA, reflux; (d) PhSO2Cl,pyridine, rt; (e) 10% Pd /C, THF–water, rt, under H2; (f) PhNCO, NEt3, THF, rt, 37% for 4a, 19% for 4b.
F
F
b
a
CO2Et
Bn
N
CO2Et
N
N
N
Bn
Bn
CO2Et
N
H
N
CO2Et
15
14
16
F
F
F
F
NH
O
d
F
F
f
e
c
OH
OH
Bn N
OH
Bn
N
N
Bn
CO2Et
17
18
19
O
S
O
N
O
O
S
O
F
F
O
S
O
g
h
N
N
O
O
F
F
F
F
N
O
NH
N
N
Bn
H
20
21
4c
Scheme 4. Synthesis of Difluorinated Compounds 4c. Reagents and conditions a) 1H-benzotriazole, formalin, MeOH, rt, 16 h; b) BrCF2CCO2Et, Zn, TMSCl, THF, rt, 2 h, 49%; c)
LDA, THF, rt, 1 h, 38%; d) 6NHCl, 110 °C, 3 h, 46%; e) 2-aminoethanol, toluene, p-TSA, reflux; f) PhSOCl2,pyridine, rt, 3 h, 39% over 2 steps; g) 20% Pd(OH)2 / C, EtOH, under H2,
78%; h) PhNCO, THF, rt, 15 min. 23%.
with Selectfluor provided monofluorinated piperidinone 13.25
Treatment of 13 in the same way as the preparation of 3 afforded
desired compounds 4a and 4b. These monofluorinated compounds
4a and 4b were easily separated in 2:1 ratio by silica gel column
chromatography. The stereochemistry of 4b was confirmed by X-
ray crystallographic analysis.
Difluorinated compound 4c was prepared starting from mate-
rial 14 (Scheme 4). Unsaturated ester 17 was prepared through
three sequential steps, Mannich type reaction, Refortmatsky reac-
tion and Dieckmann cyclization.26 Treatment of compound 17 in
6 N HCl gave ketal 18. Cyclization of the ketal 18 with aminoetha-
nol furnished spiro-oxazolidine 19, which was stable enough to be

6412
T. Fujimoto et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6409–6413
Table 2
OX2R/1R Antagonistic Activities, Selectivity Against OX1R, Human Metabolic Stabilities, Water Solubility, and Lipophilicity.
O
N
S
O
O
O
R1
R2
N
NH
compd (R1, R2)
OX-2a IC50 (nM)
OX-1a IC50 (nM)
Selectivity (OX-1/OX-2)
HLMb (mL/min/mg)
JP1c (mg/mL)
JP2c (mg /mL)
log D
3 (H, H)
4a (H, F)
4b (F, H)
4c (F, F)
710
170
220
1000
6300
280
2500
>10000
8.9
1.6
11
43
34
2
<0.07
45
8.5
1.7
34
12
18
1.82
2.04
1.50
1.93
>10
84
21
a
b
c
Antagonist activity.
HLM = metabolic stability by the incubation with human liver microsomes.
see Ref.27
Table 3
OX2R/1R Antagonistic Activities, Human Metabolic Stabilities, Water Solubility, and Lipophilicity.
O
S
R
N
O
O
F
O
N
NH
cpds
R
OX-2a IC50 (nM)
OX-1a IC50 (nM)
Selectivity (OX-1/OX-2)
HLMb (mL/min/mg)
JP1c (mg /mL)
JP2c (mg /mL)
log D
4b
4d
4e
4f
H
220
130
87
2500
2300
1600
1500
11
18
18
450
2
64
4
8.5
2.1
0.49
5.9
12
1.50
1.75
1.63
1.35
3-OMe
4-OMe
3,4-di(OMe)
2.4
0.58
4.5
3.3
<1
a
b
c
Antagonist activity.
HLM = metabolic stability by the incubation with human liver microsomes.
see Ref.27
isolated by purification through silicagel chromatography. This
result suggested that fluorine atoms stabilized the aminal sub-
structure. Subsequent four steps gave the desired compound 4c.
The profiles of compounds 3 and 4a–4c were shown in Table 2.
Fluorinated compounds 4a–4f described below were evaluated as
racemic mixtures. Solubility in the stomach and intestine simula-
tion fluid as the first fluid (JP1) and the second fluid (JP2) of the
Japanese Pharmacopoeia was assessed.27 All compounds 4a–4c
showed better solubility than 3. This improvement may have re-
sulted from a decrease in crystallinity because compounds 4b
and 4c had lower melting point and 4a is an amorphous solid.28
JP2 is a buffer solution which mimics pH of intestine fluid. There-
fore better solubility of compound 4a–4c in JP2 would be advanta-
geous for oral administration. Compound 3 was not found in JP1,
however, 4a–4c were detected in reasonable concentration in
JP1. Since JP1 is an acidic solution, the finding suggests improved
stability of compound 4a–4c in acidic condition.
Lipophilicity (log D) of compound 4b is lower than that of 3, 4a,
and 4c. The decreased lipophilicity may contribute to the better
human metabolic stability of 4b than the other compounds.
Though it is not clear why only lipophilicity of 4b is decreased,
we speculated that the stereochemical environment of fluorine
atom was likely responsible by enhancing the dipole moment.29
Finally, we investigated substituents of the phenylsulfonamide of
4b in order to further improve potency against OX2R and selectivity
against OX1R. Our investigation showed that introduction of meth-
oxy group at 3- or 4- position (4d, 4e) could achieve good results for
both issues (Table 3). These results led us to prepare 3,4-dimethoxy
compound 4f, with hope of a synergistic effect. As expected, OX2R
antagonistic activity of 4f reached single-digit nanomolar (3.3 nM)
and the selectivity against OX1R was improved 40-fold over com-
pound 4b. While solubility was slightly decreased, human metabolic
stability of 4f was improved probably because 3,4- dimethoxy group
is known as one of the best overall performing groups for improving
HLM among disubstituted phenyl moieties.30
Monofluorinated compounds 4a and 4b showed improved
antagonistic activity against OX2R compared to 3. However, the
activity of difluorinated compound 4c was comparable with 3.
Compound 4a diminished the selectivity against OX1R, while cor-
responding stereoisomer 4b showed improved selectivity against
OX1R (11-fold).
In summary, we have discovered a highly potent, novel, selec-
tive OX2R antagonist 4f. It is noteworthy that the beneficial im-
pacts of fluorine atom on spiropiperidine (4b) led to a compound
with favorable drug-like properties such as potency, selectivity,
HLM, solubility, stability, and lipophilicity. Multi-faceted optimiza-

T. Fujimoto et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6409–6413
6413
16. PSA and c log P were calculated by Physchem Batch (Ver. 10) produced by
Advanced Chemistry Development, Inc.
tion starting from compound 2 resulted in compound 4f with
much improved drug like properties (LE: 0.31 (2) vs 0.35 (4f);
LLE: 3.56 (2) vs 6.82 (4f); LELP: 9.90 (2) vs 3.86 (4f)).
17. (a) Mensch, J.; Oyarzabal, J.; Mackie, C.; Augustijins, P. J. Pharm. Sci. 2009, 98,
4429; (b) Di, L.; Kerns, E. H.; Carter, G. T. Expert Opin. Drug Discov. 2008, 3, 677;
(c) Clark, D. E. Ann. Rep. Med. Chem. 2005, 40, 403; (d) Wager, T. T.;
Chandrasekaran, R. Y.; Hou, X.; Troutman, M. D.; Verhoest, P. R.; Villalobos,
A.; Will, Y. A. C. S. Chem. Neurosci. 2010, 1, 420.
Supplementary data
18. Metabolic stabilities were determined by the described method below.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.094.
Liver Metabolic Stability Assay Conditions
References and notes
Condition
Method
1. Sakurai, T.; Amemiya, A.; Ishii, M.; Matsuzaki, I.; Chemelli, R. M.; Tanaka, H.;
Williams, S. C.; Richardson, J. A.; Kozlowski, G. P.; Wilson, S.; Arch, J. R.;
Buckingham, R. E.; Haynes, A. C.; Carr, S. A.; Annan, R. S.; McNulty, D. E.; Liu, W.
S.; Terrett, J. A.; Elshourbagy, N. A.; Bergsma, D. J.; Yanagisawa, M. Cell 1998, 92,
573.
2. Date, Y.; Ueta, Y.; Yamashita, H.; Yamaguchi, H.; Matsukura, S.; Kangawa, K.;
Sakurai, T.; Yanagisawa, M.; Nakazato, M. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
748.
Substrate
1 lM
Concentration
Microsomal protein
concentration
Co-enzyme
Temperature
Quench Solvent
0.2 mg/mL
NADPH-regenerating systems
37 °C
acetonitrile (1:1)
3. Peyron, C.; Tighe, D. K.; van den Pol, A. N.; de Lecea, L.; Heller, H. C.; Sutcliffe, J.
G.; Kilduff, T. S. J. Neurosci. 1998, 18, 9996.
4. Nambu, T.; Sakurai, T.; Mizukami, K.; Hosoya, Y.; Yanagisawa, M.; Goto, K. Brain
Res. 1999, 827, 243.
5. Marcus, J. N.; Aschkenasi, C. J.; Lee, C. E.; Chemelli, R. M.; Saper, C. B.;
Yanagisawa, M.; Elmquist, J. K. J. Comp Neurol. 2001, 435, 6.
6. (a) Lee, M. G.; Hassani, O. K.; Jones, B. E. J. Neurosci. 2005, 25, 6716; (b)
Estabrooke, I. V.; McCarthy, M. T.; Ko, E.; Chou, T. C.; Chemelli, R. M.;
Yanagisawa, M.; Saper, C. B.; Scammell, T. E. J. Neurosci. 2001, 21, 1656.
7. (a) White, C. L.; Ihii, Y.; Mendoza, T.; Upton, N.; Stasi, L. P.; Bray, G. A.; York, D.
A. Peptides 2005, 26, 2331; (b) Haynes, A.; Champan, H.; Taylor, C.; Moore, G. B.;
Cawthorne, M. A.; Tadayyon, M.; Chapham, J. C.; Arch, J. R. S. Regul. Pept. 2002,
104, 153.
Incubation time points 0, 20 min
Detection
Calculations
discrete analysis using LC/PDA
CL (
t; time, 20 (min)
l
L/min/mg) = 1000 Â (1-R)/t/m
m; microsomal protein, 0.2 (mg/mL)
R; parent remaining
Criteria
Stable: <50
Moderate: 50–100
Unstable: >100 L/min/mg
l
L/min/mg
lL/min/mg
l
8. Kang, J.-E.; Lim, M. M.; Bateman, R. J.; Lee, J. J.; Smyth, L. P.; Cirrito, J. R.; Fujiki,
N.; Nishino, S.; Holtzman, D. M. Science 2009, 326, 1005.
9. Jenck, F. Tetrahydroisoquinoline Derivatives to Enhance Memory Function.
WO2007/105177(A1).
10. Jenck, F. Tetrahydroisoquinoline Derivatives to Treating Post-Traumatic Stress
Disorders. WO2009/047723(A2).
11. Johnson, O. L.; Truitt, W.; Fitz, S. D.; Minick, P. E.; Dietrich, A.; Sanghani, S.;
Träskman-Bendz, L.; Goddard, A. W.; Brundin, L.; Shekhar, A. Nat. Med. 2010,
16, 111.
12. De Lecea, L.; Jones, B. E.; Boutrel, B.; Borgland, S. L.; Nishino, S.; Bubser, M.;
DiLeone, R. J. Neurosci. 2006, 26, 10372.
13. Coleman, P. J.; Renger, J. J. Expert Opin. Ther. Patents 2010, 20, 307. and
references cited therein.
19. Kerns, E. H.; Di, L. Drug-like Properties: Concepts, Structure Design and Methods
2008, 137.
20. (a) Kunz, I. D.; Chen, K.; Sharp, K. A. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 9997;
(b) Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discov. Today 2004, 9, 430; (c)
Abad-Zapatero, C. Expert Opin. Drug Discov. 2007, 2, 469.
21. (a) Leeson, P. D.; Springthorpe, B. Nature Rev. Drug Discov. 2007, 6, 881; (b)
Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.;
Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Bioorg. Med. Chem. Lett. 2009, 19,
4406.
14. (a) Brisbare–Roch, C.; Dingemanse, J.; Koberstein, R.; Hoever, P.; Aissaoui, H.;
Flores, S.; Mueller, C.; Nayler, O.; van Gerven, J.; de Haas, S. L.; Hess, P.; Qiu, C.;
Buchmann, S.; Schertz, M.; Weller, T.; Fischli, W.; Clozel, M.; Jenck, F. Nat. Med.
2007, 13, 150; (b) Hoever, P.; Dehaas, S.; Chiossi, E.; Van Gerven, J. Sleep 2008,
31, 12. Abst 0116; GSK press release: http://www.gsk.com/media/
pressreleases/2011/2011_pressrelease_10019.htm.; (d) Coleman, P. J.; Cox, C.
D.; Breslin, M. J.; Schreier, J. D.; Roecker, A. J.; Whitman, D. B.; Mercer, S. P.;
Bergman, J. P.; Brashear, K. M.; McGaughey, G. G.; Bednar, R. A.; Lemaire, W.;
Doran, S. M.; Fox, S. V.; Garson, S. L.; Harrell, C. M.; Kraus, R. L.; Murphy, K.;
Reiss, D. R.; Cui, D.; Li, C.; Prueksaritanont, T.; Roller, S.; Tang, C.; Stevens, J.;
Tannenbaum, P.; Young, S. D.; Koblan, K. S.; Hartman, G. D.; Renger, J. J. (MEDI-
37) 239th ACS National Meeting & Exposition March 21–25, San Francisco,
California 2010.; (e) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.;
McGaughey, G. B.; Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.;
Lemaire, W.; Bruno, J. G.; Reiss, D. R.; Harrell, C. M.; Murphy, K. L.; Garson, S. L.;
Doran, S. M.; Prueksaritanont, T.; Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T.
D.; Cui, D.; Hartman, G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.;
Coleman, P. J. J. Med. Chem. 2010, 53, 5320; (f) Winrow, C. J.; Gotter, A. L.; Cox,
C. D.; Doran, S. M.; Tannernbaum, P. L.; Breslin, M. J.; Garson, S. L.; Fox, S. V.;
Harrell, C. M.; Stevens, J.; Reiss, D. R.; Cui, D.; Coleman, P. J.; Renger, J. J. J.
Neurogenetics 2011, 25, 52.
22. Keserü, G. M.; Makara, G. M. Nature Rev. Drug Discov. 2009, 8, 203.
23. In this Letter, we calculated LLE and LELP by measured log D as lipophilicity;
Ligand efficiency (LE) is the binding energy per heavy atom (kcal molÀ1) =
D G/
number of heavy atoms = À1.36 log (OX2R IC50)/number of heavy atoms;
Ligand lipophilicity efficiency (LLE) = Àlog (OX2R IC50) – log D; LELP = log D/LE.
24. Ishikawa, M.; Hashimoto, Y. J. Med. Chem. 2011, 54, 1539.
25. Cox, C. D.; Coleman, P. J.; Breslin, M. J.; Whitman, D. B.; Garbaccio, R. M.; Fraley,
M. E.; Hartman, G. D.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.;
Lobell, R. B.; Tao, W.; Davide, J. P.; Diehl, R. E.; Abrams, M. T.; South, V. J.; Huber,
H. E.; Kohl, N. E.; Torrent, M.; Prueksaritanont, T.; Li, C.; Slaughter, D. E.; Mahan,
E.; Fernandez-Metzler, C.; Yan, Y.; Kuo, L. C. J. Med. Chem. 2008, 51, 4239.
26. Remen, L.; Bezencon, O.; Richard-Bildstein, S.; Bur, D.; Prade, L.; Corminboeuf,
O.; Boss, C.; Grisostomi, C.; Sifferlen, T.; Strickner, P.; Hess, P.; Delahaye, S.;
Treiber, A.; Weller, T.; Binkert, C.; Steiner, B.; Fischli, W. New classes of potent
and bioavailable human renin inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 6762.
27. The Japanese Pharmacopoeia Fourteenth Edition
28. Melting point: 201–202 °C (3); 188–189 °C (4b); 138–139 °C (4c).
29. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3; (b) Böhm, H.-J.; Banner, D.;
Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637.
30. Lewis, M. L.; Cucurull-Sanchez, L. J. Comput Aided Mol Des 2009, 23, 97.
15. Dugovic, C.; Shelton, J. E.; Aluisio, L. E.; Fraser, I. C.; Jiang, X.; Sutton, S. W.;
Bonaventure, P.; Yun, S.; Li, X.; Lord, B.; Dvorak, C. A.; Carruthers, N. I.;
Lovenberg, T. W. J. Pharmacol. Exp. Ther. 2009, 330, 142.