Selective and dual action orally active inhibitors of thrombin and factor Xa

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 10, 2007, Pages 2927-2930

  Young, Robert J ^a   Brown, David ^a   Burns Kurtis, Cynthia L ^b   Chan, Chuen ^a   Convery, Máire A ^a   Hubbard, Julia A ^a   Kelly, Henry A ^a   Pateman, Anthony J ^a   Patikis, Angela ^a   Senger, Stefan ^a   Shah, Gita P ^a   Toomey, John R ^b   Watson, Nigel S ^a   Zhou, Ping ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

^b GLAXOSMITHKLINE   (United States)

Author keywords

Dual inhibitor; Factor Xa; Oral; Thrombin

Indexed keywords

BLOOD CLOTTING FACTOR 10A INHIBITOR; THROMBIN INHIBITOR;

ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG POTENCY; DRUG SYNTHESIS; HYDROGENATION; MALE; NONHUMAN; RAT;

ANIMALS; DOGS; FACTOR XA; FIBRINOLYTIC AGENTS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MORPHOLINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; THROMBIN;

EID: 34247333018     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.03.080     Document Type: Article

References (24)

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20. fXa inhibitory activities were determined using Rhodamine 110, bis-(CBZ-glycylglycyl-l-arginine amide) as the fluorogenic substrate; as described in Ref. 2b; standard deviations: 1, 1 nM; 2, 49 nM; 3, 1 nM. Thrombin inhibitory activities were similarly determined using rhodamine 110, bis-(CBZ-l-valyl-l-prolyl-l-arginine amide) as described in Ref. 5b; standard deviations: 1, 22 nM; 2, 3 nM, 3, 1 nM. Standard deviations are derived from at least n ≥ 2 experiments for both assays.
21. Anticoagulant activities were determined in the prothrombin time (PT) and activated partial thromboplastin time (aPTT) assays; details are described in Refs. 2b and 5b. Standard deviations in PT assay: 1, 0.04 μM; 2, 0.39 μM; 3, 0.04 μM. Standard deviations in aPTT assay: 1, 0.01 μM; 2, 0.22 μM; 3, 0.04 μM. Standard deviations are derived from at least n ≥ 2 experiments for both assays.
22. The formulation used for both iv and po dosing to rat and dog was a 5:95% (v/v) mixture of DMSO and 50:50 PEG-200/sterile water. For all animal studies, serial blood samples were collected into heparinised containers at various time-points and blood centrifuged to yield plasma. These studies used three animals for each (iv/po) leg, except n = 2 rat data for 2 and 3.
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