9-Hydroxyazafluorenes and their use in thrombin inhibitors

Journal of Medicinal Chemistry

Volumn 48, Issue 7, 2005, Pages 2282-2293

  Stauffer, Kenneth J ^a   Williams, Peter D ^a   Selnick, Harold G ^a   Nantermet, Philippe G ^a   Newton, Christina L ^a   Homnick, Carl F ^a   Zrada, Matthew M ^a   Lewis, S Dale ^a   Lucas, Bobby J ^a   Krueger, Julie A ^a   Pietrak, Beth L ^a   Lyle, Elizabeth A ^a   Singh, Rominder ^a   Miller Stein, Cynthia ^a   White, Rebecca B ^a   Wong, Bradley ^a   Wallace, Audrey A ^a   Sitko, Gary R ^a   Cook, Jacquelyn J ^a   Holahan, Marie A ^a   Stranieri Michener, Maria ^a   Leonard, Yvonne M ^a   Lynch Jr , Joseph J ^a   McMasters, Daniel R ^a   Yan, Youwei ^b   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b Structural Biology

Author keywords

[No Author keywords available]

Indexed keywords

3 AZA 9 HYDROXY 9 FLUORENYLCARBONYLPROLYL 2 AMINOMETHYL 5 CHLOROBENZYLAMIDE; 3 AZA 9 HYDROXYFLUOREN 9 YLCARBONYLPROLYL 2 AMINOMETHYL 5 CHLOROBENZYLAMIDE; 9 HYDROXY 9 FLUORENYLCARBONYLPROLYL 2 AMINOMETHYL 5 CHLOROBENZYLAMIDE; 9 HYDROXY 9 FLUORENYLCARBONYLPROLYL 4 AMINOCYCLOHEXYLMETHYLAMIDE; 9 HYDROXYAZAFLUORENE DERIVATIVE; FERROUS CHLORIDE; FLUORENE DERIVATIVE; OXIDE; THROMBIN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG USE; HUMAN; IN VIVO STUDY; NONHUMAN; PLASMA PROTEIN BINDING; PROTHROMBIN TIME; RAT; STEREOCHEMISTRY; THROMBOSIS; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; BLOOD PROTEINS; CRYSTALLOGRAPHY, X-RAY; DOGS; FLUORENES; HALF-LIFE; HUMANS; MACACA MULATTA; MALE; MICROSOMES, LIVER; MODELS, MOLECULAR; PROLINE; PROTEIN BINDING; RATS; RATS, SPRAGUE-DAWLEY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN;

EID: 20244384721     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm049423s     Document Type: Article

References (19)

1. Hauptmann, J. Pharmacokinetics of an Emerging New Class of Anticoagulant/Antithrombotic Drugs. A Review of Small-Molecule Thrombin Inhibitors. Eur. J. Clin. Pharm. 2002, 57, 751-758.
2. Crowther, M. A.; Weitz, J. I. Ximelagatran: the first oral direct thrombin inhibitor. Expert Opin. Invest. Drugs 2004, 13, 403-413.
3. Brady, S. F.; Stauffer, K. J.; Lumma, W. C.; Smith, G. M.; Ramjit, H. G.; Lewis, S. D.; Lucas, B. J.; Gardell, S. J.; Lyle, E. A.; Appleby, S. D.; Cook, J. J.; Holahan, M. A.; Stranieri, M. T.; Lynch, J. J.; Lin, J. H.; Chen, I. W.; Vastag, K.; Naylor-Olsen, A. M.; Vacca, J. P. Discovery and Development of L-372, 460, a Novel Potent Orally Active Small Molecule Inhibitor of Thrombin: Co-application of Structure-Based Design and Rapid Multiple Analogue Synthesis on Solid Support. J. Med. Chem. 1998, 41, 401-406.
4. Lumma, W. C.; Witherup, K. M.; Tucker, T. J.; Brady, S. F.; Sisko, J. T.; Naylor-Olsen, A. M.; Lewis, S. D.; Freidinger, R. M. Design of Novel, Potent, Noncovalent Inhibitors of Thrombin with Nonbasic P1 Substructures. Rapid Structure-Activity Studies by Solid-Phase Synthesis. J. Med. Chem. 1998, 41, 3687-3693.
5. Rittle, K. E.; Barrow, J. C.; Nantermet, P. G.; Newton, C. L.; Krueger, J. A.; Lewis, S. D.; Lucas, B. J.; Selnick, H. G. Unexpected Enhancement of Potency With ortho-Aminoalkylbenzylamides in the P1 Position. Bioorg. Med. Chem. Lett. 2003 13, 3477-3482.
6. Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, B. J.; Baskin, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, E. A.; Appleby, S. D.; Chen, I. W.; Dancheck, K. B.; Vacca, J. P. Potent Noncovalent Thrombin Inhibitors that Utilize the Unique Amino Acid D-Dicyclohexylalanine in the P3 Position. Implications on Oral Bioavailability and Antithrombotic Activity. J. Med. Chem. 1997, 40, 1565-1569.
7. Nelson, T. D.; LeBlond, C. R.; Frantz, D. E.; Matty, L.; Mitten, J. V.; Weaver, D. G.; Moore, J. C.; Kim, J.; Boyd, R.; Kim, P.-Y.; Gbewonyo, K.; Brower, M.; Sturr, M.; McLaughlin, K.; McMasters, D. R.; Kress, M. H.; McNamara, J. M.; Dolling, U. H. The Stereoselective Synthesis of a Potent Thrombin Inhibitor by a Novel P2-P3 Lactone Ring Opening J. Org. Chem. 2004, 69, 3620-3627.
8. Prostakov, N. S.; Soldatenkov, A. T.; Kolyadina, N. M.; Obynochnyi, A. A.; Azafluorenes. Synthesis and Conversions. Russian Chemical Reviews 1997, 66, 121-138.
9. Plater, M. J.; Kemp, S.; Lattmann, E.; Heterocyclic Free Radicals. Part 1.4,5-Diazafluorene Derivatives of Koelsch's Free Radical: An EPR and Metal-Ion Complexation Study. J. Chem. Soc., Perk. Trans, 1 2000, 971-979.
10. Evans, D. A.; Truesdale, L. K.; Carroll, G. L. Cyanosilylation of aldehydes and ketones. A convenient route to cyanohydrin derivatives. J. Chem. Soc., Chem. Commun. 1973, 55.
11. Grunewald, G. L.; Brouillette, W. J.; Finney, J. A.; Synthesis of α-Hydroxyamides Via the Cyanosilylation of Aromatic Ketones. Tetrahedron Lett. 1980, 21, 1219-1220.
12. Mazaleyrat, J.-P.; Wakselman, M.; Formaggio, F.; Crisma, M.; Toniolo, C. Synthesis of terminally protected 9-amino-4,5-diazafluorene-9-carboxylic acid, the first rigid, transition-metal receptor, disubstituted glycine. Tetrahedron Lett. 1999, 40, 6245-6248.
13. Comins, D. L.; Stroud, E. D.; Herrick, J. J.; Regioselective Addition of Grignard Reagents to the 1-Phenoxycarbonyl Salts of Alkyl Nicotinates. Heterocycles 1984, 22, 151.
14. Epsztajn, J.; Plotka, M. W.; Grabowska, A. Application of organolithium compounds in organic synthesis. Part 19. Synthetic strategies based on aromatic metalation. A concise regiospecific synthesis of 3-halogenated picolinic and isonicotinic acids. Synth., Commun. 1997, 27, 1075-1086.
15. DuPriest, M. T.; Schmidt, C. L.; Kuzmich, D.; Williams, S. B.; A Facile Synthesis of 7-Halo-5H-indeno[1,2-b]pyridines and -pyridin-5-ones. J. Org. Chem. 1986, 51, 2021-2023.
16. Wang, P.; Layfield, R.; Landon, M.; Mayer, R. J.; Ramage, R.; Transfer active ester condensation: A novel technique for peptide segment coupling. Tetrahedron Lett. 1998, 39, 8711-8714.
17. Lewis, S. D.; Ng, A. S.; Baldwin, J. J.; Fusetani, N.; Naylor, A. M.; Shafer, J. A. Inhibition of thrombin and other trypsin-like serine proteases by cyclotheonamide. Thromb. Res. 1993, 70, 173-190.
18. Lewis, S. D.; Ng, A. S.; Lyle, E. A.; Mellott, M. J.; Appleby, S. D.; Brady, S. F.; Stauffer, K. J.; Sisko, J. T.; Mao, S. S.; Veber, D. F.; Nutt, R. F.; Lynch, J. J.; Cook, J. J.; Gardell, S. J.; Shafer, J. A. Inhibition of thrombin by peptides containing lysyl-alpha-keto carbonyl derivatives. Thromb. Haemost. 1995, 74, 1107-1112.
19. Schumacher, W. A.; Steinbacher, T. E.; Heran, C. L.; Seiler, S. M.; Michel, I. M.; Ogletree, M. L. Comparison of thrombin active site and exosite inhibitors and heparain in experimental models of arterial and venous thrombosis and bleeding. J. Pharmacol. Exp. Therap. 1993, 267, 1237-1242.