The discovery of orally available thrombin inhibitors: Optimisation of the P1 pharmacophore

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 8, 1999, Pages 1103-1108

  Ambler, John ^a   Bentley, David ^a   Brown, Lyndon ^a   Dunnet, Karen ^a   Farr, Dave ^a   Janus, Diana ^a   Le Grand, Darren ^a   Menear, Keith ^a   Mercer, Mark ^a   Talbot, Mark ^a   Tweed, Morris ^a   Wathey, Bernard ^a  

^a NOVARTIS HORSHAM RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

THROMBIN INHIBITOR;

ARTICLE; LIPOPHILICITY; X RAY SPECTROMETRY;

ANIMALS; BIOLOGICAL AVAILABILITY; HUMANS; INTESTINAL ABSORPTION; RATS; RATS, SPRAGUE-DAWLEY; THROMBIN;

EID: 0033583555     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00138-9     Document Type: Article

References (16)

1. Kaiser Brigitte. Thrombin and factor Xa inhibitors. Drugs of the Future. 1998, 23, 423-436.
2. Hirsh, J. Heparins. Fibrinolysis 1995, 9 (suppl. 1), 66-68.
3. Fareed, Jawed; Walenga, Jeanie M; Hoppensteadt, Debra; Ahsan Ahmed; Murphy, Rosemary; Weber, Stephanie; Pifarre, Roque. Pharmacological profile of low molecular weight heparins: Implications in prophylaxis and the treatment of thrombotic disorders. Low Mol. Weight Heparins Clin. Pract. 1992, 63-84. Editor(s): Doutremepuich, Christian. Publisher: Dekker, New York, N.Y.
4. Ammar, H.O.; Ghorab, M; El-Nahhas, S.A.; Makram, T. S. Improvement of the Biological Performance of Oral Anticoagulant Drugs. Part 1. Warfarin. Pharmazie 1997, 52, 627-631.
5. Wiley M. R.; Fisher, M. J. Small molecule direct thrombin inhibitors. Expert Opin. Ther. Pat. 1997, 7, 1265-1282.
6. Kikumoto, Ryoji; Tamao, Yoshikuni; Ohkubo, Kazuo; Tezuka Tohru; Tonomura, Shinji; Okamoto, Shosuke; Hijikata, Akiko. Thrombin inhibitors. 3. Carboxyl-containing amide derivatives of Nα-substituted L-arginine. J. Med. Chem. 1980, 23, 1293-1299.
7. For convenience pharmacophores residing in the S9 pocket of thrombin are referred to as P3
8. Studies relating to the discovery of the '4-amino-pyridyl' P3 pharmacophore in press
9. Bode, Wolfram; Turk, Dusan; Karshikov, Andrej. The refined 1.9-.Å. x-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human α-thrombin: Structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci. 1992, 1(4), 426-471.
10. Tucker, Thomas J.; Brady, Stephen F.; Lumma, William C; Lewis, S. Dale; Gardell, Stephen J.; Naylor-Olsen, Adel M.; Yan, Youwei; Sisko, Jack T.; Stauffer, Kenneth J.; Lucas, Bobby J.; Lynch, Joseph J.; Cook, Jacquelynn J.; Stranieri, Maria T.; Holahan, Marie A.; Lyle, Elizabeth A.; Baskin, Elizabeth P.; Chen, I-Wu; Dancheck, Kimberly B.; Krueger, Julie A.; Cooper, Carolyn M.; Vacca, Joseph P. Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position. J. Med. Chem. 1998, 41, 3210-3219.
11. Studies relating to development of novel thrombin inhibitors based on Argatroban in press. (J.Med.Chem.)
12. n>4 for all Ki values measured
13. n>3 for all APTT values measured
14. 3 chlorination of available 4-hydroxypyridine-3-sulphonic acid.
15. cLogD @pH6.2 for compound 12 is 5.10
16. cLog D values calculated using PrologD software version 2.0, Compudrug, Budapest, Hungary.