The De Novo design and synthesis of cyclic urea inhibitors of Factor Xa: Optimization of the S4 ligand

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 3, 2000, Pages 301-304

  Galemmo Jr , Robert A ^a   Wells, Brian L ^a   Rossi, Karen A ^a   Alexander, Richard S ^a   Dominguez, Celia ^a   Maduskuie, Thomas P ^a   Stouten, Pieter F W ^a   Wright, Matthew R ^a   Aungst, Bruce J ^a   Wong, Pancras C ^a   Knabb, Robert M ^a   Wexler, Ruth R ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLOOD CLOTTING FACTOR 10A; BLOOD CLOTTING FACTOR 10A INHIBITOR; LIGAND;

ARTICLE; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; IN VITRO STUDY; NONHUMAN; RABBIT; X RAY CRYSTALLOGRAPHY;

ANIMALS; CRYSTALLOGRAPHY, X-RAY; FACTOR XA; LIGANDS; MODELS, MOLECULAR; RABBITS; SERINE PROTEINASE INHIBITORS; UREA;

ORYCTOLAGUS CUNICULUS;

EID: 17344380190     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00688-5     Document Type: Article

References (26)

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23. Crystals of human thrombin-hirugen complex were prepared by the method described by Skrzypczak-Jankun, E.; Carperos, V. E.; Ravichandran, K. G.; Tulinsky, A.; Westbrook, M.; Marananore, J. M. J. Mol. Biol. 1991, 206, 755. Crystals of the thrombin-hirugen complex were transferred to a well containing a sitting solution (0.58 M sodium phosphate buffer (pH 7.2), 0.05 mM sodium azide, and 33% w:v PEG 8000). These crystals were transferred to a solution containing the inhibitor. The inhibitor solution was prepared by first dissolving the inhibitor in DMSO followed by a 10-fold dilution of the inhibitor/DMSO solution into the sitting solution. Data were collecting on an R Axis II image plate mounted on a Rigaku RU200 rotating anode; crystals diffracted to 2.2. The data were 89% complete with an R merge of 0.068. Data were refined using XPLOR (Brunger, A. T.; X-PLOR, Version 3.1. A System for X-ray Crystallography and NMR; Yale University Press: New Haven, CT) with a final R-value of 0.184. Unambigous electron density was observed for the inhibitor.
24. Compound 10 was modeled into a crystal structure of Factor Xa (ref 25) using InsightII (MSI, San Diego, CA). The starting conformation of the inhibitor was from the crystal structure of 10 in thrombin. The inhibitor was minimized in a rigid protein using the CFF98 forcefield.
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