4864-80-6Relevant articles and documents
A comparative study of warheads for design of cysteine protease inhibitors
Silva, Daniel G.,Ribeiro, Jean F.R.,De Vita, Daniela,Cianni, Lorenzo,Franco, Caio Haddad,Freitas-Junior, Lucio H.,Moraes, Carolina Borsoi,Rocha, Josmar R.,Burtoloso, Antonio C.B.,Kenny, Peter W.,Leit?o, Andrei,Montanari, Carlos A.
supporting information, p. 5031 - 5035 (2017/10/24)
The effects on potency of cruzain inhibition of replacing a nitrile group with alternative warheads were explored. The oxime was almost an order of magnitude more potent than the corresponding nitrile and has the potential to provide access to the prime side of the catalytic site. Dipeptide aldehydes and azadipeptide nitriles were found to be two orders of magnitude more potent cruzain inhibitors than the corresponding dipeptide nitriles although potency differences were modulated by substitution at P1 and P3. Replacement of the α methylene of a dipeptide aldehyde with cyclopropane led to a loss of potency of almost three orders of magnitude. The vinyl esters and amides that were characterized as reversible inhibitors were less potent than the corresponding nitrile by between one and two orders of magnitude.
Development of α-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease
Choe, Youngchool,Brinen, Linda S.,Price, Mark S.,Engel, Juan C.,Lange, Meinolf,Grisostomi, Corinna,Weston, Scott G.,Pallai, Peter V.,Cheng, Hong,Hardy, Larry W.,Hartsough, David S.,McMakin, Marsha,Tilton, Robert F.,Baldino, Carmen M.,Craik, Charles S.
, p. 2141 - 2156 (2007/10/03)
Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T. cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of α-ketoamide-, α-ketoacid-, α-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1′ residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different α-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3 A crystallographic structure of cruzain bound with one of the α-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization.
METALLOPROTEINASE INHIBITORS
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, (2008/06/13)
Compounds of general formula (I), principally characterized in that R4 is a polyether group, are water soluble matrix metalloproteinase inhibitors. STR1
