Stauffer, Kenneth J.; Williams, Peter D.; Selnick, Harold G.; Nantermet, Philippe G.; Newton, Christina L.; Homnick, Carl F.; Zrada, Matthew M.; Lewis, S. Dale; Lucas, Bobby J.; Krueger, Julie A.; Pietrak, Beth L.; Lyle, Elizabeth A.; Singh, Rominder; Miller-Stein, Cynthia; White, Rebecca B.; Wong, Bradley; Wallace, Audrey A.; Sitko, Gary R.; Cook, Jacquelyn J.; Holahan, Marie A.; Stranieri-Michener, Maria; Leonard, Yvonne M.; Lynch, Joseph J. Jr.; McMasters, Daniel R.; Yan, Youwei published the artcile< 9-Hydroxyazafluorenes and Their Use in Thrombin Inhibitors>, Category: pyridine-derivatives, the main research area is hydroxyazafluorene derivative preparation thrombin inhibitor anticoagulant thrombosis crystal structure.
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-L-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-L-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (Ki = 0.49 nM for human thrombin, 2× APTT = 0.37 μM in human plasma) and pharmacokinetic properties (F = 39%, iv T1/2 = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogs of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-L-prolyl-2-aminomethyl-5-chlorobenzylamide (I), with high potency (Ki = 0.40 nM, 2× APTT = 0.18 μM), excellent pharmacokinetic properties (F = 55%, T1/2 = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl3-induced vessel occlusions in six of six rats receiving an i.v. infusion of 10 μg/kg/min of I). The stereochem. of the azafluorenyl group in I was determined by x-ray crystallog. anal. of its N-oxide derivative bound in the active site of human thrombin.
Journal of Medicinal Chemistry published new progress about Anticoagulants. 53636-56-9 belongs to class pyridine-derivatives, and the molecular formula is C7H6BrNO2, Category: pyridine-derivatives.