Design and synthesis of a novel class of thrombin inhibitors incorporating heterocyclic dipeptide surrogates

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 12, 1997, Pages 1543-1548

  Tamura, Susan Y ^a   Semple, J Edward ^a   Reiner, John E ^a   Goldman, Erick A ^a   Brunck, Terence K ^a   Lim Wilby, Marguerita S ^a   Carpenter, Stephen H ^a   Rote, William E ^a   Oldeshulte, Gerard L ^a   Richard, Brigitte M ^a   Nutt, Ruth F ^a   Ripka, William C ^a  

^a Dendreon   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR 10A; PLASMIN; PYRIDONE DERIVATIVE; PYRIMIDINONE DERIVATIVE; SERINE PROTEINASE; THROMBIN; THROMBIN INHIBITOR; TISSUE PLASMINOGEN ACTIVATOR; TRYPSIN; URACIL DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOAVAILABILITY; CONTROLLED STUDY; DOG; DRUG DESIGN; DRUG SYNTHESIS; ENZYME INHIBITION; IN VITRO STUDY; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; STRUCTURE ACTIVITY RELATION; THROMBOSIS;

EID: 0031001455     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00258-8     Document Type: Article

References (40)

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35. 18. Hydrogenation of the uracil derivative 19 was problematic, resulting in a poorer yield for the final target 4. The yields shown for compounds 4 and 5 are unoptimized.
36. Enzyme Assays were described in Ref. 8.
37. (a) Hakanson, K.; Zhang, E.; Tulinsky, A.; Brunck, T. K.; Levy, O. E.; Semple, J. E. Manuscript in preparation.
38. (b) The crystal structure of compound 1-thrombin was used with the computer programs Insight II and Discover (MSI, San Diego, CA) to model and display the inhibitors.
39. 50 was defined as the dose required to produce a thrombus weight of half of that of control saline treated rats. A minimum of six rats were tested for each dose.
40. The absolute systemic bioavailability (%F) for compound 3 was determined in fasted, conscious, purpose-bred beagle dogs (2 males and 2 females) following separate intravenous (5 mg/kg) and oral (20 mg/kg) administration and collection of plasma samples over a defined time-course covering 6 h. The determination of plasma levels was accomplished using HPLC following post-column fluorogenic derivatization using methodologies that will be published elsewhere. The area under the plasma concentration versus time curves (AUC[0-∞]) for the oral (AUC[oral]) versus the intravenous (AUC[iv]) dosing regimens were calculated by linear trapezoidal estimation using a non-compartmental model, and were used to calculate percent oral bioavailability (%F = [(AUC[oral]/AUC[iv])/(dose iv)/(dose oral)]*100). Further details on the pharmacokinetic, pharmacodynamic and pharmacological profile of this compound will be published elsewhere.