Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 19 3561
(3) The following abbreviations are used: BABCH, 2,7-bis(4-ami-
dinobenzylidene)cycloheptan-1-one; FXa, human factor Xa; IIa,
human thrombin; trypsin, bovine cationic trypsin; PT, prothrom-
bin time; ACT, activated clotting time.
Ta ble 4. Plasma Kinetics of Selected 2,6-Diaryloxypyridines
in Nonhuman Primates Following Oral Dosinga
plasma concentration (µM)b
(4) Published examples of nonpeptide FXa inhibitors include both
dibasic and monobasic templates. Dibasic templates: (a) Naga-
hara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.-I.; Komoriya,
S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. Dibasic (Amidinoaryl)-
propanoic Acid Derivatives as Novel Blood Coagulation Factor
Xa Inhibitors. J . Med. Chem. 1994, 37, 1200-1207. (b) Sato, K.;
Kawasaki, T.; Hisamichi, N.; Taniuchi, Y.; Hirayama, F.; Koshio,
H.; Matsumoto, Y. Antithrombotic Effects of YM-60828, A Newly
Synthesized Factor Xa Inhibitor, in Rat Thrombosis Models and
Its Effects on Bleeding Time. Br. J . Pharm. 1998, 123, 92-96.
(c) Klein, S. I.; Czekaj, M.; Gardner, C. J .; Guertin, K. R.; Cheney,
D. L.; Spada, A. P.; Bolton, S. A.; Brown, K.; Colussi, D.; Heran,
C. L.; Morgan, S. R.; Leadley, R. J .; Dunwiddie, C. T.; Perrone,
M. H.; Chu, V. Identification and Initial Structural-Activity
Relationships of a Novel Class of Nonpeptide Inhibitors of Blood
Coagulation Factor Xa. J . Med. Chem. 1998, 41, 437-450. (d)
Maduskuie, T. P.; McNamara, K. J .; Ru, Y.; Knabb, R. M.;
Stouten, R. W. Rational Design and Synthesis of Novel, Potent
Bis-phenylamidine Carboxylate Factor Xa Inhibitors. J . Med.
Chem. 1998, 41, 53-62. Monobasic templates: (e) Katz, B. A.;
Clark, J . M.; Finer-Moore, J . S.; J enkins, T. E.; J ohnson, C. R.;
Ross, M. J .; Luong, C.; Moore, W. R.; Stroud, R. M. Design of
Potent Selective Zinc-mediated Serine Protease Inhibiors. Nature
1998, 391, 608-612. In addition, novel peptide FXa inhibitors
have recently been described: (f) Ostrem, J . A.; Al-Obeidi, F.;
Safar, P.; Safarova, A.; Stringer, S. K.; Patek, M.; Cross, M. T.;
Spoonamore, J .; LoCascio, J . C.; Kasireddy, P.; Thorpe, D. S.;
Sepetov, N.; Lebl, M.; Wildgoose, P.; Strop, P. Discovery of a
Novel, Potent, and Specific Family of Factor Xa Inhibitors via
Combinatorial Chemistry. Biochemistry 1998, 37, 1053-1059.
(5) (a) Phillips, G. B.; Davey, D. D.; Guilford W. J .; Eagen, K.; Ng,
H.; Pinkerton, M.; Koovakkat, S.; Wu, S.; Xu, W.; Liang, A.;
Trinh, L.; Hinchman, J .; Post, J .; Whitlow, M.; Morrissey, M.
M. Design, Synthesis, and Biological Activity of Novel Factor
Xa Inhibitors - 2. 2,6-Diphenoxypyridine Inhibitors. Presented
at the 215th American Chemical Society National Meeting,
March 29-April 2, 1998, Dallas, TX, Abstract 122. (b) Buckman,
B. O.; Mohan, R.; Liang, A.; Trinh, L.; Morrissey, M. M. Design,
Synthesis, and Biological Activity of Novel Factor Xa Inhibitors
- 6. Bicyclic Pyrimidine Analogues of 2,6-Diphenoxypyridine
Inhibitors. Presented at the 215th American Chemical Society
National Meeting, March 29-April 2, 1998, Dallas, TX, Abstract
126. (c) Griedel, B. D.; Arnaiz, D. O.; Sakata, S. T.; Shaw, K. J .;
Zhao, Z.; Dallas, J .; Koovakkat, S.; Whitlow, M.; Liang, A.; Trinh,
L.; Hinchman, J .; Post, J .; Ho, E.; Subramanyam, B.; Vergona,
R.; Walters, W.; White; Sullivan, M. E.; Morrissey, M. M. Design,
Synthesis, and Biological Activity of Novel Factor Xa Inhibitors
- 9. Benzimidazole-Based Analogues. Presented at the 215th
American Chemical Society National Meeting, March 29-April
2, 1998, Dallas, TX, Abstract 129. (d) Chou, Y.-L.; Guilford W.
J .; Koovakkat; Mohan, R.; Wu, S. C.; Liang, A.; Trinh; Morrissey,
M. M. Design, Synthesis, and Biological Activity of Novel Factor
Xa Inhibitors - 10. Optimization of Dibenzyl Cyclic Urea
Analogues. Presented at the 215th American Chemical Society
National Meeting, March 29-April 2, 1998, Dallas, TX, Abstract
130.
(6) The MOPAC progam available in the Cerius2 molecular model-
ing package, Molecular Simulations, Inc., was used for AM1
semiempirical calculations to study the relative energies for
torsion about the C-O-C bonds of 2-phenoxypyridine. A one-
dimensional torsional potential was generated for the C-O-C
torsion from 0 to 180° in steps of 10°. The energy differences for
two cases, 2-phenoxypyridine and 3-chloro-2-phenoxypyridine,
are 4.7 and 7.4 kcal/mol, respectively. The energy for the torsion
angle of 0° are lower in both cases. Stewart, J . J . P. MOPAC: A
General Molecular Orbital Package (Version 6.0), Frank J . Seiler
Research Laboratory, U.S. Air Force Academy, Colorado Springs,
CO 80840.
(7) Drendel, W. B.; Sundaralingam, M. Structures of 1,4-Bis(3,5-
dichloro-2-pyridyloxy)benzene (1), C16H8Cl4N2O2, 1,4-Bis(5-chloro-
2-pyridyloxy)benzene (2), C16H10Cl2N2O2 and 1,4-Bis(3-chloro-
2-pyridyloxy)benzene (3), C16H10Cl2N2O2. Acta Crystallogr. 1985,
C41, 950-953.
(8) (a) All new compounds gave physical and spectroscopic data
consistent with their structure. See Supporting Information for
details. (b) The general synthesis of the FXa inhibitors described
herein is outlined in the synthesis of compound 16: Pyridine
34 was coupled first with phenol 35, then with phenol 36 in the
presence of a mild base (K2CO3). The resulting nitrile was
converted to an amidine by careful treatment with ethanolic
hydrochloric acid, followed by ammonia to give compound 16.
entry
species
baboon
cynomolgus
monkey
baboon
cynomolgus
monkey
nc
1 h
2 h
3 h
4 h
6 h
1.0
2
2
4
3
0.3
0.2
0.6
0.5
0.9
0.7
1.1
1.2
29
29
3
3
0.1
0.1
0.0
0.0
0.1
0.0
0.2
0.5
0.7
0.3
33
33
baboon
cynomolgus
monkey
2
3
0.2
0.0
0.3
0.0
0.6
0.0
a
For both primate species an oral dose of 10 mg/kg in either
2% carboxymethylcellulose (cynomolgus monkeys) or 1.5% car-
boxymethylcellulose and 1% Tween 80 (baboons) was administered
b
via a nasogastric tube. Plasma concentration determined via
HPLC (cynomolgus monkey) or FXa inhibition assay (baboon).
c Number of animals.
and 3.5-fold at 1, 3, and 6 h, respectively. Following
these encouraging results, plasma levels of 2 were
determined in both primate species, following an intra-
venous dose of 0.5 mg/kg in 6% DMSO administered via
the cephalic vein (n ) 3). The beta-phase elimination
half-life is 1.5-2 h and appears to be independent of
whether plasma concentrations were determined by
HPLC or FXa inhibition analysis. The close correlation
found by comparing HPLC analysis of the parent
compound to the FXa activity assay suggests the
absence of circulating metabolites.
In this communication, we have outlined our system-
atic synthetic approach for transforming the photo-
chemically unstable FXa inhibitor (Z,Z)-BABCH (1) into
a synthetically viable inhibitor template derived from
2,6-diphenoxypyridine. While the initial inhibitors in
this series demonstrated modest FXa inhibitory potency,
optimization efforts led to a 1000-fold enhancement in
FXa inhibitory activity while maintaining excellent
selectivity against the related proteases thrombin and
trypsin. On the basis of the FXa inhibitory potency,
selectivity, and oral bioavailability data in the dog and
nonhuman primates, compound 2 has been chosen for
further preclinical evaluation. The medicinal chemistry,
biochemistry, pharmacokinetics and pharmacology of
this highly potent, selective, and orally active FXa
inhibitor will be reported in detail in future publications.
Ack n ow led gm en t. We thank Dr. Michael Hilde-
brand, Schering AG, for his help with the primate
studies and Drs. Les Browne, William Dole, and J ohn
Morser for their support and encouragement of this
effort.
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
and NMR spectral data (8 pages). Ordering information is
given on any current masthead page.
Refer en ces
(1) This manuscript is dedicated to the memory of our friend and
mentor Allan D. Rudzik, Ph.D.
(2) Shaw, K. J .; Guilford, W. J .; Dallas, J . L.; Koovakaat, S. K.;
Liang, A.; Light, D. R.; Morrissey, M. M. (Z,Z)-2,7-Bis(4-
amidinobenzylidene)cycloheptan-1-one: Identification of a Highly
Active Inhibitor of Blood Coagulation Factor Xa. J . Med. Chem.
1998, 41, 3551-3556.