Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position

Journal of Medicinal Chemistry

Volumn 40, Issue 22, 1997, Pages 3687-3693

  Tucker, Thomas J ^a   Lumma, William C ^a   Dale Lewis, S ^a   Gardell, Stephen J ^a   Lucas, Bobby J ^a   Sisko, Jack T ^a   Lynch, Joseph J ^a   Lyle, Elizabeth A ^a   Baskin, Elizabeth P ^a   Woltmann, Richard F ^a   Appleby, Sandra D ^a   Chen, I Wu ^a   Dancheck, Kimberley B ^a   Naylor Olsen, Adel M ^a   Krueger, Julie A ^a   Cooper, Carolyn M ^a   Vacca, Joseph P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

N (1 OXO 3,3 DIPHENYLPROPYL)PROLINE [(4 AMINOCYCLOHEXYL)METHYL]AMIDE; PROPIONIC ACID DERIVATIVE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ARTERY THROMBOSIS; ARTICLE; DRUG BIOAVAILABILITY; DRUG SYNTHESIS; FIBRINOLYTIC THERAPY;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; DOGS; MAGNETIC RESONANCE SPECTROSCOPY; PROPIONIC ACIDS; RATS; SPECTROMETRY, MASS, FAST ATOM BOMBARDMENT; THROMBIN;

EID: 9844258333     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970397q     Document Type: Article

References (9)

1. 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.
2. Tucker, T. J.; Lumma, W. C.; Lewis, S. D.; Gardell, S. J.; Lucas, R. J.; Baskin, E. P.; Weltmann, 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.
3. (a) Balasubramanian, N.; St. Laurent, D. R.; Federici, M. E.; Meanwell, N. A.; Wright, J. J.; Schumacher, W. A.; Seiler, S. M. Active Site-Directed Synthetic Thrombin Inhibitors: Synthesis in Vitro and in Vivo Activity Profile of BMY 44621 and Analogs. An Examination of the Role of the Amino Group in the D-Phe-Pro-Arg-H Series. J. Med. Chem. 1993, 36, 300-303.
4. (b) World Patent Appl. 9425049, 9612499, 9509858; DuPont Merck Pharmaceutical Co.
5. Leclere, G.; Decker, N.; Schwartz, J. Synthesis and Cardiovascular Activity of a New Series of Cyclohexylaralkylamine Derivatives Related to Perhexiline. J. Med. Chem. 1982, 25, 709-714.
6. Beylin, V. G.; Chen, H. G.; Dunbar, J.; Goel, O. P.; Harter, W.; Marlatt, M.; Topliss, J. G. Cyclic Derivatives of 3,3-Diphenyl-alanine (DIP) (II), Novel α-amino acids for Peptides of Biological Interest. Tetrahedron Lett. 1993, 34, 953-956.
7. Wierzbicki, M.; Hugory, P.; Duhault, J.; Cocour, F.; Boulanger, M.; Eur. Patent Appl. 518769A1; Adir et al., Fr.
8. 1 cyclohexyl ring was held fixed in the position corresponding to the crystal structure of 1.
9. Merck Research Laboratories, unreported results.