High-throughput synthesis and optimization of thrombin inhibitors via urazole α-addition and Michael addition

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 8, 2003, Pages 1445-1449

  Boatman, P Douglas ^a,c   Urban, Jan ^a   Nguyen, Minh ^a   Qabar, Maher ^a   Kahn, Michael ^b  

^a Molecumetics Ltd   (United States)

^b PACIFIC NORTHWEST RESEARCH INSTITUTE   (United States)

^c ARENA PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PYRROLE DERIVATIVE; SERINE PROTEINASE; THROMBIN; THROMBIN INHIBITOR;

ADDITION REACTION; ARTICLE; CONTROLLED STUDY; DIELS ALDER REACTION; DRUG ABSORPTION; DRUG ACTIVITY; DRUG BINDING SITE; DRUG DESIGN; DRUG POTENCY; DRUG PURITY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; MICHAEL ADDITION; PROTEIN STRUCTURE; STRUCTURE ACTIVITY RELATION;

EID: 0037451869     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00155-0     Document Type: Article

References (14)

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10. 2O (95:5) for 40 min and dried under vacuum to give the inhibitors 5-22.
11. Lyle T.A., Chen A., Appleby S.D., Freidinger R.M., Gardell S.J., Lewis S.D., Li Y., Lyle E.A., Lynch J.J., Mulichak A.M., Ng A.S., Naylor-Olsen A.M., Sanders W.M. Bioorg. Med. Chem. Lett. 1997;67.
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13. Inhibition was determined for thrombin and trypsin by florometric measurement of cleavage of the substrate tosyl-Gly-Pro-Arg-AMC at 405nM. Screening assays were performed by adjustment of the final concentration of the inhibitor to (400 nM for thrombin and 5 μM for trypsin) and measurment of the absorption of cleaved substrate versus that of a negative control.
14. i determinations were performed as described in ref 10 using eight concentrations of inhibitor and curve fitting using Prism software.