Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position

Journal of Medicinal Chemistry

Volumn 41, Issue 17, 1998, Pages 3210-3219

  Tucker, Thomas J ^a   Brady, Stephen F ^a   Lumma, William C ^a   Lewis, S Dale ^a   Gardell, Stephen J ^a   Naylor Olsen, Adel M ^a   Yan, Youwei ^a   Sisko, Jack T ^a   Stauffer, Kenneth J ^a   Lucas, Bobby J ^a   Lynch, Joseph J ^a   Cook, Jacquelynn J ^a   Stranieri, Maria T ^a   Holahan, Marie A ^a   Lyle, Elizabeth A ^a   Baskin, Elizabeth P ^a   Chen, I Wu ^a   Dancheck, Kimberly B ^a   Krueger, Julie A ^a   Cooper, Carolyn M ^a   Vacca, Joseph P ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DEXTRO CYCLOHEXYLGLYCINE PROLINE N [2 (O ETHYLACETAMIDO) 5 CHLOROBENZYL]AMIDE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BLOOD CLOT LYSIS; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; LIPOPHILICITY; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BINDING SITES; BIOLOGICAL AVAILABILITY; COMPUTER SIMULATION; CRYSTALLOGRAPHY, X-RAY; CYCLOHEXYLAMINES; DIPEPTIDES; DOGS; DRUG DESIGN; FIBRINOLYTIC AGENTS; HYDROGEN BONDING; MACACA FASCICULARIS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR STRUCTURE; RATS; RESINS, PLANT; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN;

EID: 15444357642     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9801713     Document Type: Article

References (13)

1. (1) Several comprehensive reviews of thrombin inhibitor design have recently been published: (a) Wiley, M. R.; Fisher, M. J. Small Molecule Direct Thrombin Inhibitors. Exp. Opin. Ther. Patents 1997, 7 (11), 1265-1282. (b) Ripka, W. C. New Thrombin Inhibitors in Cardiovascular Disease. Curr. Opin. Chem. Biol. 1997, 242-253.
2. Several comprehensive reviews of thrombin inhibitor design have recently been published: (a) Wiley, M. R.; Fisher, M. J. Small Molecule Direct Thrombin Inhibitors. Exp. Opin. Ther. Patents 1997, 7 (11), 1265-1282. (b) Ripka, W. C. New Thrombin Inhibitors in Cardiovascular Disease. Curr. Opin. Chem. Biol. 1997, 242-253.
3. Tucker, T. J.; Lumma, W. C.; Mulichak, A. M.; Chen, Z.; Naylor-Olsen, A. M.; Lewis, S. D.; Lucas, R.; Freidinger, R. M.; Kuo, L. C. Design of Highly Potent Noncovalent Thrombin Inhibitors that Utilize a Novel Lipophilic Binding Pocket in the Thrombin Active Site. J. Med. Chem. 1997, 40, 830-832.
4. Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, R. J.; Baskin, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, T. A.; Appleby, S. D.; Chen, I-W.; Dancheck, K. B.; Vacca, J. P. Potent Non-Covalent Thrombin Inhibitors that Utilize the Unique Amino Acid D-Dicyclohexylalanine in the P3 Position. Implications on Oral Bioavailability and Antithrombotic Efficacy. J. Med. Chem. 1997, 40, 1565-1569.
5. Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, R. J.; Baskin, E. P.; Woltmann, R.; Lynch, J. J.; Lyle, T. A.; Appleby, S. D.; Chen, I-W.; Dancheck, K. B.; Naylor-Olsen, A. M.; Krueger, J. A.; Cooper, C. M.; Vacca, J. P. The Synthesis of a Series of Potent and Orally Bioavailable Thrombin Inhibitors That Utilize 3,3-Disubstituted Propionic Acid Derivatives in the P3 Position. J. Med. Chem. 1997, 40, 3687-3693.
6. Lumma, W. C.; Wtherup, 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, Non-Covalent Inhibitors of Thrombin with Nonbasic P1 Substructures. Rapid Structure Activity Studies by Solid-Phase Synthesis. J. Med. Chem. 1998, 41, 1011-1013.
7. For the crystal structure of compound 1, a single crystal was used, diffracting to 2.3-Å resolution. The crystals were of space group C2. Full experimental details along with data collection and structure refinement parameters are provided as Supporting Information. The data will be deposited in the Protein Data Bank.
8. Booysen, J. F.; Holzapfel, C. W. A New Facile Synthesis of a Thromboxane B2 Precursor. Synth. Commun. 1995, 25 (10), 1461-1472.
9. The aldehyde starting material 6 is available commercially from Aldrich Chemical Co.
10. 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.
11. Molecular modeling was performed as follows: Models were constructed using AMF/C View (AMF is Merck proprietary software). The ligands were energy-minimized within the context of the active site using OPTiMOL with the MMFF force field.
12. For the crystal structure of compound 14b, a single crystal was used, diffracting to 1.9-Å resolution. The crystals were of space group C2. Full experimental details along with data collection and structure refinement parameters are provided as Supporting Information. The data will be deposited in the Protein Data Bank.
13. Unpublished data, Department of Drug Metabolism, Merck Research Labs, West Point, PA.