Apixaban as Inhibitor
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 22 5355
G; Ansell, J.; Deitchman D. A phase II randomized, double-blind,
five-arm, parallel-group, dose-response study of a new oral directly-
acting factor Xa inhibitor, razaxaban, for the prevention of deep vein
thrombosis in knee replacement surgery on behalf of the razaxaban
investigators. Blood 2003, 102 (11), Abstract 41.
Ogletree, and Dr. William Ewing for proofreading this manu-
script. The authors also thank Dr. Lynn Abell, Mr. Jeffrey
Bozarth, Mr. Andrew Leamy, and Ms. Tracy Bozarth for their
help in generating various enzyme data and key pharmacody-
namic measurements such as the PT/APTT and the hep test.
The authors also thank Mr. Earl Crain and Ms. Carol Watson
for their tireless efforts in generating rabbit in vivo data. Dr.
Steven Sheriff is thanked for preparing and depositing the X-ray
structure coordinates of and data for compound 40 in fXa into
the PDB and for his help in preparing Figures 2 and 3. The
authors would like to thank Dr. Paul S. Anderson for his support
and encouragement of the factor Xa program.
(8) (a) Straub, A.; Pohlmann, J.; Lampe, T.; Pernerstorfer, J.; Schlemmer,
K.-H.; Reinemer, P.; Perzborn, E.; Roehrig, S. Discovery of the novel
antithrombotic agent 5-chloro-N-({(5)-2-oxo-3-[4-(3-oxomorpholin-
4-yl)phenyl]-1-3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide
(Bay-59-7939): an oral, direct factor Xa inhibitor. J. Med. Chem.
2005, 48, 5900-5908. (b) Eriksson, B. L.; Borris, L.; Dahl, O. E.;
Haas, S.; Huisman, M. V.; Kakkar, A. K. ODIXa-HIP study
investigators. Oral, direct factor Xa inhibition with Bay-59-7939 for
the prevention of venous thromboembolism after total hip replace-
ment. J. Thromb. Haemostasis 2006, 4 (1), 121-128.
(9) (a) Liebeschuetz, J. W.; Jones, S. D.; Wiley, M. E.; Young, S. C.
Iterative structure-based screening of virtual chemical libraries and
factor Xa: finding the orally available antithrombotic candidate
LY517717. Structure-Based Drug DiscoVery 2006, 173-192. (b)
Hampton T. New oral anticoagulants show promise. JAMA, J. Am.
Med. Assoc. 2006, 295 (7), 743-744.
Supporting Information Available: Complete experimental
procedures for compounds 6, 41-47, and 13a-e,g-h and Table 8
detailing the enzyme selectivity profile of compound 40 compared
to its predecessor compounds 4 and 5. This material is available
(10) (a) McBride, B. F. A preliminary assessment of the critical differences
between novel oral anticoagulants currently in development. J. of
Clin. Pharm. 2005, 45 (9), 1004-1017. (b) Saiah, E.; Soares, C. S.
Small molecule coagulation cascade inhibitors in the clinic. Curr.
Top. Med. Chem. 2005, 5 (16), 1677-1695.
References
(1) (a) Hyers, T. M. Management of venous thromboembolism. Past
present and future. Arch. Intern. Med. 2003, 163, 759-768. (b) Stein,
P. D.; Grandison, D.; Hua, T. A. Therapeutic level of anticoagulation
with warfarin in patients with mechanical prosthetic heart valves;
review of literature and recommendations based on internal normal-
ized ratio. Postgrad. Med. J. 1994, 70 (Suppl. 1), S72-S83. (c) Hirsh,
J.; Poller, L. The international normalized ratio. A guide to
understanding and correcting its problems. Arch. Intern. Med. 1994,
154, 282-288.
(2) Weitz, J. I. Low molecular weight heparins. New Engl. J. Med. 1997,
337, 688-689.
(3) Turpie, A. G. G.; Antman, E. M. Low-molecular weight heparins in
the treatment of acute coronary syndromes. Arch. Intern. Med. 2001,
161, 1484-1490.
(4) (a) Adang, A. E. P; Rewinkel, J. B. M. A new generation of orally
active antithrombotics: comparing strategies in the GPIIb/IIIa,
thrombin and factor Xa areas. Drugs Future 2000, 25, 369-383. (b)
Rewinkel, J. B. M.; Adang, A. E. P. Strategies and progress towards
the ideal orally active thrombin inhibitor. Curr. Pharm. Des. 1999,
5, 1043-1075.
(5) Samama, M. M.; Gerotziafas, G. T. Evaluation of the pharmacological
properties and clinical results of the synthetic pentasaccharide
(fondaparinux). Thromb. Res. 2003, 109, 1-11.
(6) (a) Walenga, J. M.; Jeske, W. P.; Hoppensteadt, D.; Fareed, J. Factor
Xa inhibitors: today and beyond. Curr. Opin. InVest. Drugs 2003, 4
(3), 272-281. (b) Samama, M. M. Synthetic direct and indirect factor
Xa inhibitors. Thromb. Res. 2002, 106, V267-V273. (c) Kaiser, B.
Visions & reflections. Factor Xa, a promising target for drug
development. Cell. Mol. Life Sci. 2002, 59, 189-192. (d) Leadley,
R. J., Jr. Coagulation factor Xa inhibition: biological background
and rationale. Curr. Top. Med. Chem. 2001, 1, 151-159. (e)
Hauptmann, J.; Stu¨rzebecher, J. Synthetic inhibitors of thrombin and
factor Xa: from bench to bedside. Thromb. Res. 1999, 93, 203-
241. (f) Wong, P. C.; Crain, E. J.; Watson, C. A.; Zaspel, A. M.;
Wright, M. R.; Lam, P. Y. S.; Pinto, D. J.; Wexler, R. R.; Knabb, R.
M. Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-
active pyrazole antithrombotic agent on arterial thrombosis in rabbits.
J. Pharmacol. Exp. Ther. 2002, 303, 993-1000. (g) Wong, P. C.;
Pinto, D. J.; Knabb, R. M. Nonpeptide factor Xa inhibitors: DPC423,
a highly potent and orally bioavailable pyrazole antithrombotic agent.
CardioVasc. Drug ReV. 2002, 20 (2), 137-152. (h) Wong, P. C.;
Quan, M. L.; Crain, E. J.; Watson, C. A.; Wexler, R. R.; Knabb, R.
M. Nonpeptide factor Xa inhibitors: I. studies with SF303 and
SK549, a new class of potent antithrombotics. J. Pharmacol. Exp.
Ther. 2000, 292, 351-357.
(7) (a) Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.;
Li, R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.; Sun, J.-H.; Alexander,
R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler,
R. R. Discovery of 1-(3′-aminobenzisoxazol-5′-yl)-3-trifluoromethyl-
N-[2-fluoro-4-[(2′-dimethylamino-methyl)imidazol-1-yl]phenyl]-1H-
pyrazole-5-carboxyamide hydrochloride (razaxaban), a highly potent
and selective, orally bioavailable factor Xa inhibitor. J. Med. Chem.
2005, 48, 1729-1744. (b) Wong, P. C.; Crain, E. J.; Watson, C. A.;
Wexler, R. R.; Lam, P. Y. S.; Quan, M. L.; Knabb, R. M. Razaxaban,
a direct factor Xa inhibitor, in combination with aspirin and/or
clopidogrel improves low-dose antithrombotic activity without
enhancing bleeding liability in rabbits. J. Thromb. Thrombolysis 2007,
24 (1), 43-51. (c) Lassen, M. R.; Davidson, B. L.; Gallus, A.; Pineo,
(11) Pinto, D. J. P.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.;
Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood,
A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.;
Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam P. Y. S. Discovery
of 1-[3-aminomethyl)phenyl]-N-[3-fluoro-2′-(methylsulfonyl)-[1,1′-
biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide
(DPC423), a highly potent, selective, and orally bioavailable inhibitor
of coagulation factor Xa. J. Med. Chem. 2001, 44, 566-578.
(12) (a) Pruitt, J. R.; Pinto, D. J. P; Galemmo, R, A.; Alexander, R. S.;
Rossi, K. A.; Wells, B. L.; Drummond, S.; Bostrom, L. L.; Burdick,
D.; Bruckner, R.; Chen, H.; Smallwood, A.; Wong, P. C.; Wright,
M. R.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Lam, P. Y. S. Wexler,
R. R. Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-
N-[3-fluoro-2′-(aminosulfonyl)[1,1′-biphenyl)]-4-yl]-1H-pyrazole-5-
carboxyamide (DPC602), a potent, selective, and orally bioavailable
factor Xa inhibitor. J. Med. Chem. 2003, 46, 5298-5315. (b) Lam,
P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J.; Orwat, M. J.; Galemmo,
R. A.; Fevig, J. M.; Teleha, C. A.; Alexander, R. A.; Smallwood, A.
M.; Rossi, K. A.; Wright, M. R.; Bai, S. A.; He, K.; Luettgen, J. M.;
Wong, P. C.; Knabb, R. M.; Wexler, R. R. Structure-based design
of novel guanidine/benzamidine mimics: potent and orally bioavail-
able factor Xa inhibitors as novel anticoagulants. J. Med. Chem. 2003,
46, 4405-4418. (c) A similar approach was used in the following:
Jia, Z. J.; Wu, Y.; Huang, W.; Zhang, P.; Clizbe, L. A.; Scarborough,
R. M.; Zhu, B.-Y. 1-(2-Naphthyl)-1H-pyrazole-5-carboxamides as
potent factor Xa, inhibitors. Part 2: a survey of P4 motifs. Bioorg.
Med. Chem. Lett. 2004, 14, 1221-1227. (d) A similar interaction
was seen by the Berlex group: Adler, M.; Kochanny, M. J.; Ye, B.;
Rumennik, H.; Light, D. R.; Biancalana, S.; Whitlow, M.; Crystal
structures of two potent nonamidine inhibitors bound to factor Xa.
Biochemistry 2002, 41, 15514-15523.
(13) (a) Ames, B. N.; McCann, J.; Yamasaki, E. Methods for detecting
carcinogen and mutagenesis with the salmonella/mammalian-mi-
crosome mutagenicity test. Mutat. Res. 1975, 31, 347-364. (b) For
a review, see the following: Quillardet, P.; Hofnung, M. The SOS
chromotest: a review. Mutat. Res. 1993, 297, 235-279.
(14) (a) Obe, G.; Pfeiffer, P.; Savage, J. R. K.; Johannes, C.; Goedecke,
W.; Jeppesen, P.; Natarajan, A. T.; Martinez-Lopez, W.; Olle, G.
A.; Drets, M. E. Chromosomal aberrations: formation, identification
and distribution. Mutat. Res. 2002, 504, 17-36. (b) Krishna, G.;
Hayashi, M. In vivo rodent micronucleus assay: protocol, conduct
and data interpretation. Mutat. Res. 2000, 455, 155-166.
(15) (a) Pinto, D. J. P.; Orwat, M.; Quan, M. L.; Galemmo, R. A., Jr.;
Amparo, E.; Wells, B.; Ellis, C.; He, M. Y.; Alexander, R. S.; Rossi,
K. A.; Smallwood, A.; Wong, P. C.; Luettgen, J. M.; Rendina, A.
R.; Knabb, R. M.; Mersinger, L.; Kettner, C.; Bai, S.; He, K.; Wexler,
R. R.; Lam, P. Y. S. 1-[3-Aminobenz-isoxazol-5′-yl]-3-trifluoro-
methyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-
yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808)
a highly potent, selective, efficacious and orally bioavailable inhibitor
of blood coagulation factor Xa. Bioorg. Med. Chem. Lett. 2006, 16,
4141-4147. (b) Li, Y.-L.; Fevig, J. M.; Cacciola, J.; Buriak, J.; Rossi,
K. A.; Jona, J.; Knabb, R. M.; Luettgen, J. M.; Wong, P. C.; Bai, S.
A.; Wexler, R. R.; Lam, P. Y. S. Preparation of 1-(3-aminobenzo-
[d]isoxazol-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as potent,
selective, and efficacious inhibitors of coagulation factor Xa. Bioorg.
Med. Chem. Lett. 2006, 16 (19), 5176-5182. (c) Fevig, J. M.;