JOURNAL PRE-PROOF
O
H
N
References and notes
Cl
NH2
O
Cl
Cl
NH2
CN
a
b
c
O
NH2
1.
2.
Potts, J. T.; Gardella, T. J. Ann. N. Y. Acad. Sci. 2007, 1117, 196.
Doppelt, S. H.; Neer, R. M.; Nussbaum, S. R.; Federico, P.; Potts,
J. T., Jr.; Rosenblatt, M. Proc. Natl. Acad. Sci. USA. 1986, 83,
7557.
27
25
26
3.
Shimizu, N.; Dean, T.; Tsang, J. C.; Khatri, A.; Potts, J. T., Jr.;
Gardella, T. J. J. Biol. Chem. 2005, 280, 1797.
Morphy, R. J, Med. Chem. 2006, 49, 2969.
Tamura, T.; Noda, H.; Joyashiki, E.; Hoshino, M.; Watanabe, T.;
Kinosaki, M.; Nishimura, Y.; Esaki, T.; Ogawa, K.; Miyake, T.;
Arai, S.; Shimizu, M.; Kitamura, H.; Sato, H.; Kawabe, Y. Nat.
Commun. 2016, 7, 13384.
H
H
N
O
O
N
Cl
NC
H
N
4.
5.
d
NHBoc
N
N
+
I
28
29
30
6.
Carter, P. H.; Liu, R. Q.; Foster, W. R.; Tamasi, J. A.; Tebben, A.
J.; Favata, M.; Staal, A.; Cvijic, M. E.; French, M. H.; Dell, V.;
Apanovitch, D.; Lei, M.; Zhao, Q.; Cunningham, M.; Decicco, C.
P.; Trzaskos, J. M.; Feyen, J. H. M. Proc. Natl. Acad. Sci. USA.
2007, 104, 6846.
Low, C. M. R.; Mcdonald, L. M.; Pether, M. J.; Spencer, J.;
Tisselli, P.; Wright, P. T. WO 2008/009963 A2, Jan 24, 2008.
McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.; Gaffen,
J.; Griffin, E.; Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.;
Linney, I. D.; Low, C. M. R.; Patel, D.; Pether, M. J.; Raynor, M.;
Roberts, S. P.; Shaxted, M. E.; Spencer, J.; Steel, K. I. M.; Sykes,
D. A.; Wright, P. T.; Xun, W. J. Med. Chem. 2007, 50, 4789.
Mcdonald, I. M.; Spencer, J.; Buck, I. M.; Dunstone, D. J.; Linney,
I. D.; Tisselli. P.; Hull, R. A. D.; Austin, C.; Harper, E. A.; Sykes,
D.; Griffin, E.; Shaxted, M. WO 2007/135350 A1, Nov 29, 2007.
H
N
NHBoc
O
R
HN
HN
23 : R =
24 : R =
O
N
e
f
O
7.
8.
N
N
NC
NC
N
N
SO2Me
31
Scheme 1. Synthesis of representative compounds 23 (DS08210767) and
9.
24. Reagents and conditions: (a) cyclohexylmagnesium bromide, THF, 0 °C
to rt, 87%; (b) 2-amino-2-methyl-propanoyl chloride; hydrochloride, MeCN,
rt; (c) triethylamine, 1-butanol, reflux, 65% (for two steps); (d) tBuXphos Pd
G1, tBuXPhos, KOAc, potassium hexacyanoferrate(II) trihydrate, dioxane-
H2O, 100 °C, 76%; (e) CuI, trans-N,N'-dimethylcyclohexane-1,2-diamine,
K2CO3, dioxane, 100 °C, 93%; (f) (i) TFA, CH2Cl2, rt, 93%; (ii) ketone (for
23, tetrahydro-4H-pyran-4-one; for 24, 1-N-(methylsulfonyl)-4-piperidinone,
NaBH(OAc)3, AcOH, CH2Cl2, rt, 97% (for 23), 85% (for 24).
10. Mcdonald, I. M.; Spencer, J.; Buck, I. M.; Linney, I. D.; Pether, M.
J.; Tisselli, P.; Steel, K. I. M.; Wright, P. T. WO 2007/135417 A1,
Nov 29, 2007.
11. IC50 values were measured by cAMP assay on human PTHR1
receptor-expressing CHO-K1 cells and determined in a 8-point
dose-response curve in quadruplicate measurements at each
concentration. For the detailed experimental procedures, please
see Supplementary data.
12. clogP values were calculated using ChemBioDraw Ultra version
12.0. The distribution coefficients (log D) were measured between
1-octanol and phosphate buffered saline (pH 7.4).
13. DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.;
Pippin, D. A. Comb. Chem. High Throughput Screen. 2004, 7,
473.
14. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893.
15. Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C.
J. Med. Chem. 2010, 53, 7902.
In summary, we successfully identified the novel 1,4-
benzodiazepin-2-one-based PTHR1 antagonist DS08210767 by
means of a scaffold-hopping approach based on the structure
reported in JBF’s patent. The compound exhibited potent
antagonist activity and an ADME/PK profile that suggested good
oral bioavailability.
DS08210767 is expected to be useful for studying disorders of
calcium metabolism such as hypercalcemia and bone disease.
16. Decillis, A.; Lager, J. WO 2013/067141 A1, May 10, 2013.
17. (a) Jones, L. H.; Summerhill, N. W.; Swain, N. A.; Mills, J. E.
Med. Chem. Commun., 2010, 1, 309; (b) Senecal, T. D.; Shu, W.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52, 10035.
18. (a) Klapars, A.; Antila, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727; (b) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421; (c) Kang, S.
K.; Kim, D. H.; Pak, J. N. Synlett 2002, 427.
Table 6. Physicochemical properties and Pharmacokinetic
parameters of DS08210767.
Log
Da
Solubili
ty
M
Sc
PB CLe
Vde
(L/k
g)
T1/2 AUClast
%
F
d
f
f
(mL/min/
kg)
JP1/JP2 (%
fre
e
(h)
(h*g/m
b
)
L)
19. For the preparation of compound 30, please see Supplementary
data.
(%
)
(g/mL
)
760/50
0
4.2
3
2.9
28
2.9 46.8
4.7
1.94
27
Supplementary Material
a The distribution coefficients (log D) were measured between 1-octanol and
phosphate buffered saline (pH 7.4).
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
b JP1/JP2: Japanese pharmacopoeia first/second test fluid (pH = 1.2/6.8).
c MS: metabolic stability, remaining (%) of compound 23 after 0.5 h of
incubation with rat liver microsomes.
d PB: protein binding, unbound fractions (%) in rat plasma.
e 1 mg/kg intravenous administration in male Sprague-Dawley rats (n = 2).
Dosing formulation: DMA/Tween80/PBS (1:1:8).
f 10 mg/kg oral administration in male Sprague-Dawley rats (n = 3). Dosing
formulation: PG/Tween (4:1).
Acknowledgments
We thank Dr. Tsuyoshi Muto for suggestions on writing this
manuscript. We are also grateful to Dr. Tsuneo Deguchi for
performing pharmacokinetic experiments and Ms. Yumiko
Fujisawa for her helpful support.