4319-72-6Relevant academic research and scientific papers
Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
Lampa, Anna,Alogheli, Hiba,Ehrenberg, Angelica E.,?kerblom, Eva,Svensson, Richard,Artursson, Per,Danielson, U. Helena,Karlén, Anders,Sandstr?m, Anja
, p. 6595 - 6615 (2015/02/19)
With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1′ positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1′ macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1′ elongations. In fact, linear P2-P1′ spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
Novel peptidomimetic hepatitis C virus NS3/4A protease inhibitors spanning the P2-P1′ region
Lampa, Anna K.,Bergman, Sara M.,Gustafsson, Sofia S.,Alogheli, Hiba,Akerblom, Eva B.,Lindeberg, Gunnar G.,Svensson, Richard M.,Artursson, Per,Danielson, U. Helena,Karlen, Anders,Sandstroem, Anja
supporting information, p. 249 - 254 (2014/04/03)
Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2-P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.
