80102-23-4Relevant academic research and scientific papers
2H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design
Giroud, Maude,Kuhn, Bernd,Saint-Auret, Sarah,Kuratli, Christoph,Martin, Rainer E.,Schuler, Franz,Diederich, Fran?ois,Kaiser, Marcel,Brun, Reto,Schirmeister, Tanja,Haap, Wolfgang
, p. 3370 - 3388 (2018/05/01)
Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition (Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
Discovery of pyrrolopyrimidine inhibitors of Akt
Blake, James F.,Kallan, Nicholas C.,Xiao, Dengming,Xu, Rui,Bencsik, Josef R.,Skelton, Nicholas J.,Spencer, Keith L.,Mitchell, Ian S.,Woessner, Richard D.,Gloor, Susan L.,Risom, Tyler,Gross, Stefan D.,Martinson, Matthew,Morales, Tony H.,Vigers, Guy P.A.,Brandhuber, Barbara J.
scheme or table, p. 5607 - 5612 (2010/11/17)
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
