439117-44-9Relevant academic research and scientific papers
Improved stability of proline-derived direct thrombin inhibitors through hydroxyl to heterocycle replacement
Chobanian, Harry R.,Pio, Barbara,Guo, Yan,Shen, Hong,Huffman, Mark A.,Madeira, Maria,Salituro, Gino,Terebetski, Jenna L.,Ormes, James,Jochnowitz, Nina,Hoos, Lizbeth,Zhou, Yuchen,Lewis, Dale,Hawes, Brian,Mitnaul, Lyndon,O'Neill, Kim,Ellsworth, Kenneth,Wang, Liangsu,Biftu, Tesfaye,Duffy, Joseph L.
, p. 553 - 557 (2015/05/27)
Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replace
9-Hydroxyazafluorenes and their use in thrombin inhibitors
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 Jr., Joseph J.,McMasters, Daniel R.,Yan, Youwei
, p. 2282 - 2293 (2007/10/03)
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 analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-L-prolyl-2-aminomethyl-5- chlorobenzylamide (19b), with high potency (Ki = 0.40 nM, 2× APTT = 0.18 μM), excellent pharmacokinetic properties (F = 55%, T 1/2 = 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 intravenous infusion of 10 μg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
Low molecular weight thrombin inhibitors with excellent potency, metabolic stability, and oral bioavailability
Morrissette, Matthew M.,Stauffer, Kenneth J.,Williams, Peter D.,Lyle, Terry A.,Vacca, Joseph P.,Krueger, Julie A.,Lewis, S. Dale,Lucas, Bobby J.,Wong, Bradley K.,White, Rebecca B.,Miller-Stein, Cynthia,Lyle, Elizabeth A.,Wallace, Audrey A.,Leonard, Yvonne M.,Welsh, Denise C.,Lynch, Joseph J.,McMasters, Daniel R.
, p. 4161 - 4164 (2007/10/03)
Modification of lead compound 1 by reducing lipophilicity in the P3 group produced a series of low molecular weight thrombin inhibitors with excellent potency in functional assays, metabolic stability, and oral bioavailability. These modifications led to
Thrombin inhibitors
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, (2008/06/13)
Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, e.g. where R3 is —CH2NH2, —CH2CH2NH2, or —CH2NHC(O)OC(CH3)3.
