190904-21-3Relevant articles and documents
Design, synthesis, and SAR of a series of activated protein C (APC) inhibitors with selectivity against thrombin for the treatment of haemophilia
Bach, Peter,Knerr, Laurent,Fjellstr?m, Ola,Hansson, Kenny,Mattsson, Christer,Gustafsson, David
, p. 821 - 827 (2014/02/14)
A design strategy was used to identify inhibitors of activated protein C with selectivity over thrombin featured by a basic and/or aromatic functionality for binding to the S2 pocket. Our strongest inhibitor showed an IC 50-material value and selectivity for APC vs thrombin similar to a compound previously reported in the literature. However, in contrast to the reference compound, our compound showed a retained coagulant effect of thrombin with increasing substrate concentration in a modified Calibrated Automated Thrombogram (CAT) method. This was likely related to our compound being inactive against FVIIa, while the reference compound showed an IC50 of 8.9 μM. Thus, the higher selectivity of our compound against all relevant coagulation factors likely explained its higher therapeutic potential in comparison to the reference compound. The data indicate that at least a 100-fold selectivity over other serine proteases in the coagulation cascade will be required for an effective APC inhibitor.
Technical scale synthesis of a new and highly potent thrombin inhibitor
Bernard, Harald,Buelow, Gerd,Lange, Udo E. W.,Mack, Helmut,Pfeiffer, Thomas,Schaefer, Bernd,Seitz, Werner,Zierke, Thomas
, p. 2367 - 2375 (2007/10/03)
In this account, we describe the development of an efficient and convergent process for the peptidomimetic thrombin inhibitor 1 on production plant scale. Starting from nicotinonitrile (13), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2- pyrrolidinecarboxylic acid (5) and (2R)-2-amino-3-cyclohexylpropanoic acid (29) compound 1 was obtained in 16 chemical steps. New methods had been developed for the preparation of the key intermediate dehydroproline 22 and the transformation of nitriles into amidines. The thrombin inhibitor 1 was isolated by special techniques (nanofiltration and spray drying). Almost all salts of 1 are amorphous, however, a crystalline complex was obtained with 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Saccharin).
Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics
Adang, Anton E. P.,De Man, Adrianus P. A.,Vogel, Gerard M. T.,Grootenhuis, Peter D. J.,Smit, Martin J.,Peters, Co A. M.,Visser, Arie,Rewinkel, Jos B. M.,Van Dinther, Theo,Lucas, Hans,Kelder, Jan,Van Aelst, Sjoerd,Meuleman, Dick G.,Van Boeckel, Constant A. A.
, p. 4419 - 4432 (2007/10/03)
Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED50 was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages.
