Discovery of a potent and short-acting oral calcilytic with a pulsatile secretion of parathyroid hormone

Article abstract of DOI:10.1021/ml100268k

Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandi

Full text of DOI:10.1021/ml100268k

LETTER
pubs.acs.org/acsmedchemlett
Discovery of a Potent and Short-Acting Oral Calcilytic with a Pulsatile
Secretion of Parathyroid Hormone
Yuko Shinagawa,*,† Teruhiko Inoue,† Takeo Katsushima,*,† Toshihiro Kiguchi, Taku Ikenogami,
Naoki Ogawa, Kenji Fukuda, Kazuyuki Hirata, Kazuhito Harada, Masaki Takagi, Takashi Nakagawa,
Shuichi Kimura, Yushi Matsuo, Mariko Maekawa, Mikio Hayashi, Yuki Soejima, Mitsuru Takahashi,
Masanori Shindo, and Hiromasa Hashimoto*
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
S Supporting Information
b
ABSTRACT: Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have
been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic
drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which
transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cyto-
chrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to
change the physicochemical properties of the highly lipophilic amine 1 by introduction of a
carboxylic acid group as well as further structural modifications led to the discovery of the highly
potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a signi-
ficantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral
administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the
pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.
KEYWORDS: Calcium-sensing receptor (CaSR) antagonist, calcilytics, PTH, short-acting, osteoporosis, cytochrome P450
inhibition
steoporosis is a bone disease marked by decreased bone
strength and accompanied by an increased risk of bone
Endogenous PTH is secreted from the parathyroid gland
when lowered blood levels of ionized calcium are detected by
the calcium-sensing receptor (CaSR), a G-protein coupled recep-
tor expressed on the surface of parathyroid cells.5 Thereby, the
antagonists, known as calcilytics, reduce the sensitivity of this
receptor to extracellular calcium and stimulate PTH secretion.
This outcome was first shown by an orally available calcilytic,
NPS-2143 (Figure 1).6,7 At the same time, it was also reported
that the long acting profile of this compound resulted in
sustained high PTH levels and no net increase of bone mass.
Therefore, research has been focused on the development of a
CaSR antagonist with rapidly absorption and a short acting
pharmacokinetic profile to achieve a PTH secretion pattern
similar to that of the exogenously injected form.
Although many CaSR antagonists have been reported in the
literature to date,8-16 the proof of concept in humans was
recently shown by ronacarelet17 and JTT-30518 (MK-5442, 15
hemisulfate) (Figure 1). We have reported a new aminopropan-
diol class of calcilytics 1 (Figure 1) which demonstrated a rapid
and transient stimulation of PTH secretion after oral adminis-
tration in rats.12,19 However, compound 1 possessed a strong
CYP2D6 inhibition (IC50 of 0.5 μM) and low bioavailability (BA,
13%). Here, we report our research efforts to improve the CYP
O
fracture, affecting more than 75 million people in EU, U.S., and
Japan.1 The current mainstream drugs for osteoporosis are anti-
resorptive agents such as bisphosphonates, estrogen, and selec-
tive estrogen receptor modulators (SERMs).2 These compounds
suppress osteoclast cell function and prevent bone loss. How-
ever, an anabolic agent which stimulates osteoblast cells and leads
to new bone formation is an attractive alternative.
The bone strength defined by bone density and quality is
maintained through the balance of old bone resorption and
new bone formation, known as bone remodeling. Parathyroid
hormone (PTH) is a key intrinsic agent regulating bone
remodeling in either the catabolic or the anabolic pathways,
depending on the pattern of exposure to the hormone. Inter-
mittent exposure to PTH is important to stimulate new bone
formation and leads to anabolic effects, while prolonged
exposure to elevated PTH levels increases bone turnover and
results in bone loss.3 Since daily subcutaneous injection of
teriparatide, the recombinant 1-34 amino acid fragment of
human parathyroid hormone (PTH), improved bone mineral
density (BMD) in the lumbar spine and reduced bone fracture
rates in patients with postmenopausal osteoporosis,4 anabolic
agents have received much attention. Currently, two injectable
human PTH peptides, teriparatide and Preotact (hPTH 1-84),
are on the market, but no orally administered anabolic drug
is available.
Received: November 9, 2010
Accepted: December 21, 2010
Published: December 29, 2010
r
2010 American Chemical Society
238
dx.doi.org/10.1021/ml100268k ACS Med. Chem. Lett. 2011, 2, 238–242
|

ACS Medicinal Chemistry Letters
LETTER
Table 1. In Vitro hCaSR Antagonist Activity of the Amino-
propandiol Derivatives
Figure 1. Structures of selected calcilytics.
inhibition and the low BA, which led to the discovery of short-
acting oral calcilytic 15 with pulsatile secretion of PTH.
Molecules that are basic in character and highly lipophilic are
conducive to CYP2D6 inhibition and also block the human
ether-a-go-go related gene (hERG) ion channel.20 NPS-2143
and compound 1 exhibit both of these physicochemical char-
acteristics. NPS-2143 has been reported to inhibit CYP2D6 and
hERG strongly.10 In an examination of the metabolites of 1 in
rats, two products in which the methyl group on the benzene ring
was oxidized to either the alcohol or to the carboxylic acid were
identified. Both these oxidative metabolites have reduced lipo-
philicity compared to that of parent compound 1. While the
alcohol 2 still inhibited CYP2D6 (IC50 of 1.2 μM), the inhibitory
potency of carboxylic acid 3 (diastereomixture) toward CYP2D6
activity was significantly weakened (IC50 > 10 μM). Although 3
exhibited significantly decreased CaSR antagonist activity, changing
the position of the COOH group to the meta site (4) restored the
antagonist activity (IC50 of 1.0 μM) and reduced CYP2D6
inhibition (IC50 > 10 μM). In light of this result, we attempted
to introduce a carboxylic acid group into the molecule in an effort to
develop an orally active aminopropandiol calcilytic without the
unfavorable off-target activities. The compounds described in this
paper were tested in the human CaSR antagonist assay (PC12h
cells reporter gene assay) (Table 1) and by measurement of PTH
secretion in rats (Table 2), as previously reported.19
The initial phase of the investigation focused on defining the
site in the molecule where a COOH group could be introduced
without affecting CaSR antagonist activity, as compared to 1.
Benzoic acid analogue 5, having a COOH group at the para posi-
tion of the left benzene ring, and 6, a methyl analogue of 3 with a
benzylic substituent, exhibited significantly decreased antagonist
activity, while the phenylacetic acid derivative 7 maintained
the antagonist activity (IC50 of 2.2 μM). Further extension of
the methylene chain to the phenylpropionic acid structure (8)
increased inhibitory potency 100-fold (IC50 of 0.024 μM), which
is comparable to that of compound 1, indicating that the COOH
group in the area ortho to the site of attachment of the amino-
propandiol chain could be accommodated. Compound 8 showed
significantly reduced CYP2D6 inhibition (IC50 of 9.6 μM).
To define the optimum position for the COOH group, we
prepared three carboxylic acids 9-11 in which the position of
the COOH groups were fasten by the rigid biphenyl structure.
Two of those, 10 and 11, with meta and ortho substituents,
respectively, showed antagonist activities that were comparable
to or more potent than those of 1. On the other hand, para
substituent (9) displayed poor activity. Since these compounds are
diastereomixtures at the benzylic Me substituent, we prepared an
a In vitro hCaSR antagonist activity was determined in PC12h cells, as
described in ref 24. Values are means of three experiments. b Reference
12. c Diastereomixture.
R,R-isomer of 11 (compound 12) with the same configuration
as that of compound 1 . The R,R-enantiomer 12 showed the
most potent antagonist activity of all tested analogues (IC50 of
0.004 μM) and a reduced CYP2D6 inhibition (IC50 > 10 μM).
We also examined the PTH secretion activity of 8 and 12
(Table 2). An oral dose of 12 at 10 mg/kg in rats elicited PTH 1-34
levels that were comparable to those obtained with a 30 mg/kg
dose of 1. At the lower dose of 3 mg/kg, compounds 8 and 12
exhibited similar PTH secretion activities. These results confirmed
that these carboxylic acid derivatives are orally active. However,
their potencies in PTH secretion activity were not largely
improved compared to that of 1, indicating that BA was not
much improved in these compounds. In fact, a pharmacokinetic
239
dx.doi.org/10.1021/ml100268k |ACS Med. Chem. Lett. 2011, 2, 238–242

ACS Medicinal Chemistry Letters
LETTER
Table 2. In Vivo PTH Secretion Activity of the Selected
Scheme 1a
Compounds in Rats
PTH secretiona
compd
1 mg/kg
3 mg/kg
10 mg/kg
8
NT
-
þ
NT
þþ
NT
NT
þþ
12
13
14
15
þ
þ
-
þþ
þþ
þþ
þþ
a Increases of serum PTH 1-34 levels (Δ) were compared with levels
observed in control rats treated with vehicle. The peak levels, measured
at 15 or 30 min after oral administration of the compounds in rats (n =
5), were compared with the levels observed in animals treated with
compound 1 (30 mg/kg, po, ∼2-4-fold increases). þþ, >80% of com-
pound 1; þ, 50-80% of compound 1; -, <50% of compound 1; NT,
not tested.
a Reagents and conditions: (a) (R)-(-)-glycidyl 3-nitrobenzenesulfo-
nate, NaH, DMF or THF-DMSO, rt; (b) [1,1-dimethyl-2-(2-naphtha-
lenyl)ethyl]amine (20), EtOH, 60 °C, 12 h; (c) 20, LiClO4, CH3CN or
toluene, reflux, 12 h; (d) KOH, ethylene glycol, 160 °C, 8 h; (e) 2N
NaOH aq, MeOH; (f) 4-formylphenylboronic acid, Pd(PPh3)4,
Na2CO3, EtOH-toluene reflux; (g) MnO2, KCN, EtOH, rt; (h) 2N
NaOH aq, THF-MeOH.
observed with exogenous PTH injection,21,22 indicating that com-
pound 15 could be a bone anabolic agent for osteoporosis. A bone
anabolic effect of compound 15 on ovariectomized (OVX) rats has
been observed (manuscript submitted).23 A pharmacokinetic study
of 15 showed that the short-acting character of this compound was
well correlated with the pharmacokinetic profile. It was rapidly
absorbed after oral administration in rats (1 mg/kg, Tmax of 0.5 h,
Cmax of 475 ng/mL) and disappeared shortly thereafter (T1/2 of
1.8 h). The BA was dramatically improved (64%). The strong
CYP2D6 inhibition activity observed with compound 1 (IC50 of
0.5 μM) was significantly reduced in compound 15 (IC50 of
11 μM). Compound 15 showed a weak inhibition for β2-adrenergic
receptor binding (IC50 of 1.7 μM) and did not show binding
inhibition for R2-adrenergic receptor, dopamine transporter (D1),
and serotonin receptors up to 10 μM.
The compounds investigated in this study were synthesized
as shown in Schemes 1 and 2. Alcohols 1612 were converted to
the glycidyl ethers 17-19 by alkylation with (R)-(-)-glycidyl
3-nitrobenzensulfonate in the presence of NaH in DMF or in
THF-DMSO. Epoxy-opening reaction of 17 or 18 with 1,1-
dimethyl-2-(2-naphthalenyl)ethylamine 2019 gave the amino-
alcohol 21 or 22, respectively. Hydrolysis of the nitrile group
in 21 by KOH in ethylene glycol or the ester group in 22 by aq
NaOH in MeOH afforded the carboxylic acids 3-6. Biphenyl
carboxylic acids 9-11 were prepared from the glycidyl ether 19
in four steps as follows. Suzuki coupling of 19 with 4-formyl-
phenylboronic acid and subsequent oxidation of the aldehyde by
MnO2 in the presence of KCN in EtOH gave the esters 23, which
were reacted with an amine 20 and hydrolyzed to the corre-
sponding carboxylic acids 9-11. Optically active compounds 7,
Figure 2. Time courses of PTH 1-34 levels after oral administration of
15 hemisulfate in rats. Data are expressed as mean values ( standard
deviation, n = 5.
study of 12 in rats showed low BA (6.4%). We considered that
the naphthyl structure on the right-hand side of the molecules
might contribute to the low BA of this series. Among the
compounds examined to improve BA, 4-chloro-3-fluorophenyl
derivative 13 showed a better potency in vivo compared to 12
(PTH secretion levels at 3 mg/kg dose of 13 were similar to those
at 10 mg/kg dose of compound 12), although the antagonist
potency was lower (IC50 of 0.023 μM).
Another concern for the metabolism of these derivatives was
the formation of conjugated metabolites (e.g., glucuronic acid
conjugation). We hypothesized that the introduction of a Me
group ortho to the COOH on the phenyl ring (compound 14)
might cause steric hindrance and interfere with the glucuronate
conjugate reaction. As a result, compound 14 exhibited a sustai-
ned antagonist activity but an improved potency in vivo com-
pared to 12. Finally, all these modifications were successfully
combined, as exemplified by compound 15, which showed a high
antagonist activity (IC50 of 0.012 μM) and a potentiated PTH
secretion activity in vivo (10-fold more potent than 12).
A PTH secretion time course study after oral administration of
15 in rats was conducted (Figure 2). Compound 15 afforded
elevated endogenous PTH 1-34 levels rapidly, transiently, and
in a dose-dependent manner at a dose as low as 1 mg/kg. A maximal
level was observed at 15 min and was restored to baseline within
2 h. The PTH secretion pattern is in good agreement with that
240
dx.doi.org/10.1021/ml100268k |ACS Med. Chem. Lett. 2011, 2, 238–242

ACS Medicinal Chemistry Letters
LETTER
Scheme 2a
’ ACKNOWLEDGMENT
The authors thank our Analytical Research and Development
Laboratories for collecting analytical data and Dr. Jun-ichi Haruta
for his continuous encouragement.
’ REFERENCES
(1) Report of a WHO Scientific Group. Prevention and management
of osteoporosis; W. H. O. Tech. Rep. Ser.; World Health Organization:
Geneva, 2003; Vol. 921, pp. 1-164.
(2) Deal, C. Osteoporosis therapies Bisphosphonates, SERMs,
PTH, and new therapies. Clin. Rev. Bone Miner. Metab. 2005, 3, 125–141.
(3) Kimmel, D. B.; Bozzato, R. P.; Kronis, K. A.; Coble, T.;
Sindrey, D.; Kwong, P.; Recker, R. R. The effect of recombinant
human (1-84) or synthetic human (1-34) parathyroid hormone on
the skeleton of adult osteopenic ovariectomized rats. Endoclinology
1993, 132, 1577–1584.
(4) Neer, R. M.; Arnaud, C. D.; Zanchetta, J. R.; Prince, R.; Gaich,
G. A.; Reginster, J. Y.; Hodsman, A. B.; Eriksen, E. F.; Ish-Shalom, S.;
Genant, H. K.; Wang, O.; Mitlak, B. H. Effect of Parathyroid Hormone
(1-34) on Fractures and Bone Mineral Density in Postmenopausal
Women with Osteoporosis. N. Engl. J. Med. 2001, 344, 1434–1441.
(5) Brown, E. M.; MacLeod, R. J. Extracellular Calcium Sensing and
Extracellular Calcium Signaling. Physiol. Rev. 2001, 81, 239–297.
(6) Nemeth, E. F.; Delmar, E. C.; Heaton, W. L.; Miller, M. A.;
Lambert, L. D.; Conklin, R. L.; Gowen, M.; Gleason, J. G.; Bhatnagar,
P. K.; Fox, J. Calcilytic Compounds: Potent and Selective Ca2þ Receptor
Antagonists That Stimulate Secretion of Parathyroid Hormone.
J. Pharm. Exp. Ther. 2001, 299, 323–331.
(7) Gowen, M.; Stroup, G. B.; Dodds, R. A.; James, I. E.; Votta, B. J.;
Smith, B. R.; Bhatnagar, P. K.; Lago, A. M.; Callahan, J. F.; Del Mar,
E. G.; Miller, M. A.; Nemuth, E. F.; Fox, J. Antagonizing the parathyroid
calcium receptor stimulates parathyroid hormone secretion and bone
formation in osteopenic rats. J. Clin. Invest. 2000, 105, 1595–1604.
(8) Yang, W.; Ruan, Z.; Wang, Y.; Van Kirk, K.; Ma, Z.; Arey, B. J.;
Cooper, C. B.; Seethala, R.; Feyen, J. H. M.; Dickson, J. K., Jr. Discovery
and Structure-Activity Relationships of Trisubstituted Pyrimidines/
Pyridines as Novel Calcium-Sensing Receptor Antagonists. J. Med.
Chem. 2009, 52, 1204–1208.
a Reagents and conditions: (a) ethyl tributylstannyl acetate, Pd(PPh3)4,
toluene, reflux, 5 h; (b) methyl acrylate, P(o-tolyl)3, Pd(OAc)3, Et3N,
CH3CN, reflux, 12 h; (c) H2, Rh-Al2O3 (cat), MeOH; (d) 4-methoxy-
carbonylphenylboronic acid, Pd(PPh3)4, Na2CO3, EtOH-toluene re-
flux; (e) 4-(methoxycarbonyl)-3-methylphenylboronic acid pinacol
ester (25),24 PdCl2(dppf), Na2CO3, EtOH-toluene reflux; (f) [1,1-
dimethyl-2-(2-naphthalenyl)ethyl]amine (20), LiClO4, CH3CN or
toluene, reflux; (g) 2 N NaOH aq, THF-MeOH; (h) 2-(4-chloro-3-
fluorophenyl)-1,1-dimethylethylamine (30), LiClO4, toluene, reflux.
8, and 12-15 were synthesized from chiral glycidyl ether 24
(prepared from the corresponding chiral alcohol by the same
method described in Scheme 1). Either a coupling reaction of 24
with ethyl tributylstannyl acetate in the presence of Pd(PPh3)4, a
Heck reaction of 24 with methyl acrylate followed by hydro-
genation of the double bond in the presence of Rh/Al2O3, or
Suzuki couplings with the corresponding boronic acids24,25 gave
the epoxides 26-29, which were converted to 12-15 by epoxy-
opening reaction with the corresponding amine 20 or 3024 and
subsequent hydrolysis of the ester, respectively.
(9) Balan, G.; Bauman, J.; Bhattacharya, S.; Castrodad, M.; Healy,
D. R.; Herr, M.; Humphries, P.; Jennings, S.; Kalgutkar, A. S.; Kapinos,
B.; Khot, V.; Lazarra, K.; Li, M.; Li, Y.; Neagu, C.; Oliver, R.; Piotrowski,
D. W.; Price, D.; Qi, H.; Simmons, H. A.; Southers, J.; Wei, L.; Zhang, Y.;
Paralkar, V. M. The Discovery of Novel Calcium Sensing Receptor
Negative Allosteric Modulators. Bioorg. Med. Chem. Lett. 2009, 19,
3328–3332.
(10) Marquis, R. W.; Lago, A. M.; Callahan, J. F.; Rahman, A.; Dong,
X.; Stroup, G. B.; Hoffman, S.; Gowen, M.; DelMar, E. G.; Van
Wagenen, B. C.; Logan, S.; Shimizu, S.; Fox, J.; Nemeth, E. F.; Roethke,
T.; Smith, B. R.; Ward, K. W.; Bhatnagar, P. Antagonists of the Calcium
Receptor. 2. Amino Alcohol-Based Parathyroid Hormone Secretago-
gues. J. Med. Chem. 2009, 52, 6599–6605.
In conclusion, we have discovered a potent and short-acting
oral aminopropandiol calcilytic 15, bearing a biphenylcarboxylic
acid structure. The strong CYP2D6 inhibition seen in the proto-
type compound 1 was significantly reduced by the introduction
of a COOH group. Modification of the naphthylethylamine
part and the incorporation of a biphenylcarboxylic acid moiety
bearing a substituent on the position ortho to the COOH provided
a significant improvement of BA in rats. Oral administration of 15
in rats led to a pulsatile secretion of endogenous PTH, which is a
required profile for a bone anabolic agent. Compound 15 is now in
a phase 2 clinical study.
(11) Didiuk, M. T.; Griffith, D. A.; Benbow, J. W.; Liu, K. K.; Walker,
D. P.; Bi, F. C.; Morris, J.; Guzman-Perez, A.; Gao, H.; Bechle, B. M.;
Kelley, R. M.; Yang, X.; Dirico, K.; Ahmed, S.; Hungerford, W.;
DiBrinno, J.; Zawistoski, M. P.; Bagley, S. W.; Li, J.; Zeng, Y.; Santucci,
S.; Oliver, R.; Corbett, M.; Olson, T.; Chen, C.; Li, M.; Paralkar, V. M.;
Riccardi, K. A.; Healy, D. R.; Kalgutkar, A. S.; Maurer, T. S.; Nguyen,
H. T.; Frederick, K. S. Short-Acting 5-(Trifluoromethyl)pyrido[4,3-
d]pyrimidin-4(3H)-one Derivatives as Orally-Active Calcium-Sensing
Receptor Antagonists. Bioorg. Med. Chem. Lett. 2009, 19, 4555–4559.
(12) Shinagawa, Y.; Inoue, T.; Hirata, K.; Katsushima, T.; Nakagawa,
T.; Matsuo, Y.; Shindo, M.; Hashimoto, H. New Aminopropandiol
Derivatives as Orally Available and Short-Acting Calcium-Sensing
Receptor Antagonists. Bioorg. Med. Chem. Lett. 2010, 20, 3809–3813.
(13) Southers, J. A.; Bauman, J. N.; Price, D. A.; Humphries, P. S.;
Balan, G.; Sagal, J. F.; Maurer, T. S.; Zhang, Y.; Oliver, R.; Herr, M.;
Healy, D. R.; Li, M.; Kapinos, B.; Fate, G. D.; Riccardi, K. A.; Paralkar,
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details for the
b
synthesis and characterization of the tested compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail addresses: yuko.shinagawa@jt.com (Y.S.), takeo.kat-
sushima@jt.com (T.K.), hiromasa.hashimoto@jt.com (H.H.).
Author Contributions
†These three authors contributed equally to this work.
241
dx.doi.org/10.1021/ml100268k |ACS Med. Chem. Lett. 2011, 2, 238–242

ACS Medicinal Chemistry Letters
LETTER
V. M.; Brown, T. M.; Kalgutkar, A. S. Metabolism-Guided Design of
Short-Acting Calcium-Sensing Receptor Antagonists. ACS Med. Chem.
Lett. 2010, 1, 219–223.
(14) Widler, L.; Altmann, E.; Beerli, R.; Breitenstein, W.; Bouhelal,
R.; Buhl, T.; Gamse, R.; Gerspacher, R.; Halleux, C.; John, M. R.;
00
Lehmann, H.; Kalb, O.; Kneissel, M.; Missbach, M.; Muller, I. R.;
Reidemeister, S.; Renaud, J.; Taillardat, A.; Tommasi, R.; Weiler, S.;
Wolf, R. M.; Seuwen, K. 1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-
ones: A Novel Series of Potent Calcium-Sensing Receptor Antagonists.
J. Med. Chem. 2010, 53, 2250–2263.
(15) Gerspacher, M.; Altmann, E.; Beerli, R.; Buhl, T.; Endres, R.;
Gamse, R.; Kameni-Tcheudji, J.; Kneissel, M.; Krawinkler, K. H.;
Missbach, M.; Schmidt, A.; Seuwen, K.; Weiler, S.; Widler, L. Penta-
substituted benzimidazoles as potent antagonists of the calcium-
sensing receptor (CaSR-antagonists). Bioorg. Med. Chem. Lett. 2010,
20, 5161–5164.
(16) Yoshida, M.; Mori, A.; Inaba, A.; Oka, M.; Makino, H.;
Yamaguchi, M.; Fujita, H.; Kawamoto, T.; Goto, M.; Kimura, H.; Baba,
A.; Yasuma, T. Synthesis and structure-activity relationship of tetra-
hydropyrazolopyrimidine derivatives—A novel structural class of potent
calcium-sensing receptor antagonists. Bioorg. Med. Chem. 2010, 18,
8501–8511.
(17) Fitzpatrick, L. A.; Brennan, E.; Kumar, S.; Matheny, C.; Yi, B.;
McLaughlin, M.; Phillips, J.; Skordos, L.; Ethgen, D. Ronacaleret, a
Novel Calcium-Sensing Receptor Antagonist, Demonstrates Potential
as an Oral Bone-Forming Therapy in Healthy Postmenopausal Women.
ASBMR 30th Annual Meeting_FINAL_Abstract_Book 2008, 50, 1174.
(18) Fukumoto, S.; Nakamura, T.; Nishizawa, Y.; Hayashi, M.;
Matsumoto, T. Randomized, Single-Blinded Placebo-Controlled Study
of a Novel Calcilytic, JTT-305, in Patients with Postmenopausal
Osteoporosis. J. Bone Miner. Res. 24 (Suppl. 1). Available at http://
www.asbmr.org/Meetings/AnnualMeeting/AbstractDetail.aspx?
aid=f7a434e5-ad26-4aa0-930d-5bca406c9317. Accessed July 1, 2009.
(19) Shinagawa, Y.; Katsushima, T.; Nakagawa, T. Calcium Receptor
Antagonists. WO 2002/014259.
(20) Gleeson, M. P. Generation of a Set of Simple, Interpretable
ADMET Rules of Thumb. J. Med. Chem. 2008, 51, 817–834.
(21) Teriparatide injection (rDNA origin). Data on file, Eli Lilly,
USA, 2002 [online]. Available at http://www.accessdata.fda.gov/drug-
satfda_docs/nda/2002/21-318_FORTEO_BioPharmr.pdf. Accessed
July 1, 2010.
(22) Rubin, M. R.; Bilezikian, J. P. Parathyroid Hormone as an
Anabolic Skeletal Therapy. Drugs 2005, 65, 2481–2491.
(23) Kimura, S. Manuscript submitted.
(24) Shinagawa, Y.; Inoue, T.; Kiguchi, T.; Ikenogami, T.; Ogawa,
N.; Fukuda, K.; Nakagawa, T.; Shindo, M.; Soejima, Y. CaSR Antagonist.
WO 2004/094362.
(25) Shinagawa, Y.; Inoue, T.; Kiguchi, T.; Ikenogami, T.; Ogawa,
N.; Nakagawa, T.; Shindo, M.; Soejima, Y. CaSR Antagonist. WO 2004/
106280.
242
dx.doi.org/10.1021/ml100268k |ACS Med. Chem. Lett. 2011, 2, 238–242