Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: Rapid structure-activity studies by solid-phase synthesis

Journal of Medicinal Chemistry

Volumn 41, Issue 7, 1998, Pages 1011-1013

  Lumma Jr , William C ^a   Witherup, Keith M ^a   Tucker, Thomas J ^a   Brady, Steven F ^a   Sisko, John T ^a   Naylor Olsen, Adel M ^a   Dale Lewis, S ^a   Lucas, Bobby J ^a   Vacca, Joseph P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; BENZYLAMINE DERIVATIVE; DICHLOROMETHANE; DICYCLOHEXYLCARBODIIMIDE; L 373102; L 373722; L 377009; RESIN; THROMBIN INHIBITOR; TRIFLUOROACETIC ACID; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; MOLECULAR MODEL; PROTON NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; X RAY ANALYSIS;

ANTITHROMBINS; BENZHYDRYL COMPOUNDS; DRUG DESIGN; MODELS, MOLECULAR; PYRROLES; STRUCTURE-ACTIVITY RELATIONSHIP; THROMBIN;

EID: 15444357766     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9706933     Document Type: Article

References (8)

1. Kimball, S. D. Challenges in the development of orally bioavailable thrombin active site inhibitors. Blood Coagul. Fibrin. 1995, 6, 511-519.
2. Hauptmann, J.; Markwardt, F. Pharmacologic aspects of the development of selective synthetic thrombin inhibitors as anticoagulants. Semin. Thromb. Hemostasis 1992, 75, 200-217.
3. Tucker, T. J.; Lumma, W. C.; Mulichak, A. M.; Chen, Z.; NaylorOlsen, A. M.; Lewis, S. D.; Lucas, R.; Freidinger, R. M.; Kuo, L. C. The 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. Bruce D. Dorsey et al., unpublished work of these laboratories.
5. Lyle, T. A.; Chen, Z.; Appleby, S. D.; Freidinger, R. M.; Gardell, S. J.; Lewis, S. D.; Li, Y.; Lyle, E. A.; Lynch, J. J., Jr.; Mulichak, A. M.; Ng, A. S.; Naylor-Olsen, A. M.; Sanders, W. M. Synthesis, evaluation, and crystallographic analysis of L-371,912: A potent and selective active-site thrombin inhibitor. Bioorg. Med. Chem. Lett. 1997, 7, 67-72.
6. This work is the subject of a patent, WO97/15190; see also: De Grado, W. F.; Kaiser, E. T. J. Org. Chem. 1980, 45, 1295.
7. Several other research teams have reported covalent inhibitors with neutral P-1 moieties (see refs 1 and 2).
8. Modeling methods are described fully in ref 3. X-ray structural studies will be published elsewhere.