Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives

Journal of Medicinal Chemistry

Volumn 43, Issue 4, 2000, Pages 649-663

  Sall, Daniel J ^a   Bailey, Dianna L ^a   Bastian, Jolie A ^a   Buben, John A ^a   Chirgadze, Nickolay Y ^a   Clemens Smith, Amy C ^a   Denney, Michael L ^a   Fisher, Matthew J ^a   Giera, Deborah D ^a   Gifford Moore, Donetta S ^a   Harper, Richard W ^a   Johnson, Lea M ^a   Klimkowski, Valentine J ^a   Kohn, Todd J ^a   Lin, Ho Shen ^a   McCowan, Jefferson R ^a   Palkowitz, Alan D ^a   Richett, Michael E ^a   Smith, Gerald F ^a   Snyder, David W ^a   Takeuchi, Kumiko ^a   Toth, John E ^a   Zhang, Minsheng ^a,b   more..

^a ELI LILLY AND COMPANY   (United States)

^b BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [2 [[5 [6 HYDROXY 3 [[3 METHOXY 4 [(1 PYRROLIDINYL)METHYL]PHENYL]METHYL]BENZO[B]THIOPHEN 2 YL]PYRID 2 YL]OXY]ETHYL]PYRROLIDINE; 1 [4A,8A]PERHYDROISOQUINOLYLPROLYLARGINYL ALDEHYDE; 3 BROMO 4 [(1 PYRROLIDINYL)METHYL]PHENYL 6 METHOXY 2 [4 [2 (1 PYRROLIDINYL) ETHOXY]PHENYL]BENZO[B]THIOPHEN 3 YL KETONE; 6 HYDROXY 3 [3 METHOXY 4 [(1 PYRROLIDINYL)METHYL]BENZYL] 2 [4 [2 (1 PYRROLIDINYL)ETHOXY]PHENYL]BENZO[B]THIOPHENE; BENZOTHIOPHENE DERIVATIVE; THROMBIN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG POTENCY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; THROMBOSIS;

ANIMALS; ANTICOAGULANTS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG EVALUATION, PRECLINICAL; HUMANS; MODELS, MOLECULAR; PYRROLIDINES; RATS; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; THROMBIN; THROMBOSIS;

EID: 17744415875     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9903388     Document Type: Article

References (44)

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32. A detailed account of the X-ray crystallography studies performed on this series of thrombin inhibitors will be provided in a future publication.
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35. Unpublished observations.
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37. Experiments with the rat AV shunt model were performed with slight modifications of Smith, J. R.; White A. M. Br. J. Pharmacol. 1982, 77, 29. Drug or vehicle was infused for 15 min prior to opening the shunt and was continued for an additional 15 min after the shunt was opened. Net clot weights from drug-treated animals were expressed as a percent of the vehicle-treated animals run in the same experiments.
38. Plasma pharmacokinetic studies were conducted in male Sprague-Dawley rats in which saline solutions of inhibitor 28c and 31c were administered intravenously at 5 mg/kg via tail vein injection. Serial blood samples were obtained from the orbital sinus at 5, 15, 30, 60, 120, 180, and 240 min post dose from 2 or 3 rats per time point. Plasma samples were extracted using Bond Elute C8 (Varian) cartridges and assayed for drug concentrations by an HPLC method using a methanol/30 mM ammonium acetate buffer (pH 4) gradient.
39. Ruterbories, K. J.; Hanssen, B. R.; Lindstrom, T. D. Unpublished results.
40. max), area under the plasma concentration versus time curve (AUC), half-life, and volume of distribution were determined from the plasma concentration-time profiles using standard analysis.
41. Four male Fischer 344 rats were administered a 5 mg/kg dose of compound 31c via the tail vein. At 10, 30, 120, and 300 min after dosing, the rats were sacrificed and samples of blood, liver, kidney, lung, and heart were obtained. Plasma was obtained by centrifugation of whole blood. Tissue samples were rinsed in cold water, blotted dry, weighed, and homogenized in one volume of purified water. Protein was precipitated using methanol. The methanolic supernates were made acidic and partitioned against hexane, and then they were made basic and extracted using methylene chloride. Sample extracts were concentrated, reconstituted, and analyzed by HPLC. Concentrations of 31c in each sample were determined in relationship to standards prepared in each tissue matrix. To determine whether glucuronide metabolites were also present, the methanolic supernates from liver and kidney samples were diluted with water and extracted using C8 Bond Elute cartridges, prior to analysis by HPLC.
42. Unpublished observations.
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44. The preparation of the amino acids used in the synthesis of compounds 4b, 4c, 4d, 4f, 4g, 23a, and 27 is included in the Supporting Information.