Potent noncovalent thrombin inhibitors that utilize the unique amino acid D-dicyclohexylalanine in the P3 position. Implications on oral bioavailability and antithrombotic efficacy

Journal of Medicinal Chemistry

Volumn 40, Issue 11, 1997, Pages 1565-1569

  Tucker, Thomas J ^a   Lumma, William C ^a   Lewis, S Dale ^a   Gardell, Stephen J ^a   Lucas, Bobby J ^a   Baskin, Elizabeth P ^a   Woltmann, Richard ^a   Lynch, Joseph J ^a   Lyle, Elizabeth A ^a   Appleby, Sandra D ^a   Chen, I Wu ^a   Dancheck, Kimberley B ^a   Vacca, Joseph P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,3 DICYCLOHEXYLALANYLPROLINE N [(4 AMINOCYCLOHEXYL)METHYL]AMIDE; ARGATROBAN; DICYCLOHEXYLAMINE DERIVATIVE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOG; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; INTRAVENOUS DRUG ADMINISTRATION; LIPOPHILICITY; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; THROMBOSIS;

ANIMALS; BIOLOGICAL AVAILABILITY; DIPEPTIDES; DOGS; FIBRINOLYTIC AGENTS; LIPID METABOLISM; MALE; MOLECULAR STRUCTURE; PARTIAL THROMBOPLASTIN TIME; PHENYLALANINE; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN; THROMBOSIS;

EID: 0343443219     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970140s     Document Type: Article

References (7)

1. Tucker, T. J.; Lumma, W. C.; Naylor-Olsen, A. M.; Lewis, S. D.; Lucas, R.; Freidinger, R. M.; Mulichak, A. M.; Chen, Z.; 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.
2. There is a previous patent that generically describes the use of this amino acid as a P3 ligand in thrombin inhibitors: Teger-Nilsson, A. C. E.; Bylund, R. E. WO9311152-A1, 1995.
3. Boc and Fmoc-D-diphenylalanine are commercially available from Synthetech, Inc., Albany, OR. Prior to this material becoming commercially available, racemic diphenylalanine was prepared according to Cheng et al.; Synthesis and Biological Activity of Ketomethylene Pseudopeotide Analogs as Thrombin Inhibitors. J. Med. Chem. 1992, 35, 3364-3370 and references cited therein.
4. Full experimental details for the preparation of CBZ-protected trans-4- (aminomethyl)cyclohexylamine are provided in the patent claiming this series of compounds: Brady, S. F.; Feng, D. M.; Freidinger, R. M.; Lumma, W. C.; Lyle, T. A.; Sanderson, P. E. J.; Stauffer, K. J.; Tucker, T. J.; Vacca, J. P. US 5, 510, 369, 1996.
5. Details of these assays are provided in several previous publications from our group: (a) Lewis, S. D.; Ng, A. S.; Baldwin, J. J.; Fusetani, N.; Naylor, A. M.; Shafer, J. S. Inhibition of Thrombin and Other Trypsin-like Serine Proteinases by Cyclotheonamide A. Thromb. Res. 1993, 70, 173-190. (b) 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-a Keto Carbonyl Derivatives. Thromb. Haemostasis 1995, 74, 1107-1112.
6. Details of these assays are provided in several previous publications from our group: (a) Lewis, S. D.; Ng, A. S.; Baldwin, J. J.; Fusetani, N.; Naylor, A. M.; Shafer, J. S. Inhibition of Thrombin and Other Trypsin-like Serine Proteinases by Cyclotheonamide A. Thromb. Res. 1993, 70, 173-190. (b) 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-a Keto Carbonyl Derivatives. Thromb. Haemostasis 1995, 74, 1107-1112.
7. Details of the experimental determination of this parameter are provided in the publications cited in ref 5.