Orally active thrombin inhibitors. Part 1: Optimization of the P1-moiety

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 10, 2006, Pages 2641-2647

  Mack, Helmut ^a   Baucke, Dorit ^b   Hornberger, Wilfried ^a   Lange, Udo E W ^a   Seitz, Werner ^b   Höffken, H Wolfgang ^b  

^a ABBOTT GMBH AND CO KG   (Germany)

^b BASF SE   (Germany)

Author keywords

Amidine; Anticoagulant; Factor IIa inhibitor; Serine protease inhibitor; Thrombin inhibitor

Indexed keywords

1 METHYLPYRROLE; AMINOTHIOPHENE; ANTICOAGULANT AGENT; ARGININE; BENZENE DERIVATIVE; DEXTRO PHENYLPROLYLARGININE; ECARIN; FURAN; MELAGATRAN; OXADIAZOLE DERIVATIVE; OXAZOLE; PYRAZOLE; PYRIDINE; THIADIAZOLE DERIVATIVE; THIAZOLE; THIOPHENE; THIOPHENE DERIVATIVE; THROMBIN INHIBITOR; TRIAZOLE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BLOOD CLOTTING TIME; CHEMICAL STRUCTURE; DOG; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG POTENCY; EX VIVO STUDY; IN VIVO STUDY; NONHUMAN; RAT;

ADMINISTRATION, ORAL; ANIMALS; ANTITHROMBINS; DOGS; MODELS, MOLECULAR; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; X-RAY DIFFRACTION;

ANIMALIA; CANIS FAMILIARIS;

EID: 33645931993     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.02.040     Document Type: Article

References (37)

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11. For synthesis details see also Ref. 10.
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13. Modification of the P3-moiety and P4-moiety: Mack, H.; Baucke, D.; Höffken, H. W.; Hornberger, W.; Lange, U. E. W.; Seitz W. Bioorg. Med. Chem. Lett., in preparation.
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24. Synthesis of the building block 5d for the final compounds 17, 29, 32 (cf. Ref. 5f), compound 20 (cf. Ref. 5c), and compound 26 (cf. Ref. 5e).
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30. Measurement of ecarin clotting time (ECT): Venous blood is collected from rats or dogs, respectively, at the desired time after administration of the thrombin inhibitor. One hundred microliters of citrated blood is pipetted into a coagulation cuvette and incubated for 2 min at 37 °C in a coagulometer. After the addition of 100 μL of prewarmed (37 °C) ecarin reagent (Pentapharm), the time (ECT) to formation of a fibrin clot is determined.
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32. X-ray structure analysis of thrombin-inhibitor-complex of 8; X-ray crystallographic data have been deposited with the Brookhaven Protein Data Bank. Deposition code 2ANM.
33. X-ray structure analysis of thrombin-inhibitor-complex of 10; X-ray crystallographic data have been deposited with the Brookhaven Protein Data Bank. Deposition code 2FES.
34. X-ray structure analysis of thrombin-inhibitor-complex of 16; X-ray crystallographic data have been deposited with the Brookhaven Protein Data Bank. Deposition code 2FEQ.
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36. The authors have deposited the coordinates with the Brookhaven Protein Data Bank: Deposition code 1O0D (for 23) and 1NZQ (for 22).
37. Plasma levels of thrombin inhibitors were determined in dogs by means of ex vivo measurements of ECT in plasma (cf. Ref. 14). The ECT increases linearly with plasma concentration and therefore provides a suitable method for preliminary pharmacokinetic/pharmacodynamic assessment.