179524-08-4Relevant articles and documents
Design and evaluation of Trypanosoma brucei metacaspase inhibitors
Berg, Maya,Veken, Pieter Van der,Joossens, Jurgen,Muthusamy, Venkatraj,Breugelmans, Matthias,Moss, Catherine X.,Rudolf, Jana,Cos, Paul,Coombs, Graham H.,Maes, Louis,Haemers, Achiel,Mottram, Jeremy C.,Augustyns, Koen
scheme or table, p. 2001 - 2006 (2010/10/01)
Metacaspase (MCA) is an important enzyme in Trypanosoma brucei, absent from humans and differing significantly from the orthologous human caspases. Therefore MCA constitutes a new attractive drug target for antiparasitic chemotherapeutics, which needs further characterization to support the discovery of innovative drug candidates. A first series of inhibitors has been prepared on the basis of known substrate specificity and the predicted catalytic mechanism of the enzyme. In this Letter we present the first inhibitors of TbMCA2 with low micromolar enzymatic and antiparasitic activity in vitro combined with low cytotoxicity.
COMPOUNDS AND COMPOSITIONS AS CHANNEL ACTlVATING PROTEASE INHIBITORS
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Page/Page column 29, (2008/12/08)
The invention provides compounds and pharmaceutical compositions thereof, which are useful for modulating channel activating proteases, and methods for, using such compounds to treat, ameliorate or prevent a condition associated with a channel activating protease, including but not limited to prostasin, PRSS22, TMPRSS11 (e.g., TMPRSS11B, TMPRSS11E), TMPRSS2, TMPRSS3, TMPRSS4 (MTSP-2), matriptase (MTSP-1), CAP2, CAP3, trypsin, cathepsin A, or neutrophil elastase.
Aromatic heterocyclic derivatives as enzyme inhibitors
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Page column 67, (2010/02/04)
The present invention discloses peptide aldehydes which are potent and specific inhibitors of thrombin, their pharmaceutically acceptable salts, pharmaceutically acceptable compositions thereof, and methods of using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis.
Rational design, synthesis, and serine protease inhibitory activity of a novel P1-argininal derivative featuring a conformationally constrained P2-P3 bicyclic lactam moiety
Tamura, Susan Y.,Goldman, Erick A.,Brunck, Terence K.,Ripka, William C.,Semple, J. Edward
, p. 331 - 336 (2007/10/03)
Based on molecular modeling and judicious combination of the salient topographic features of the recently discovered P3-lactam derivative 1 with the P2-prolyl derivatives 2a,b, the novel thrombin inhibitor 3a was designed. Inhibitor 3a incorporates a fused bicyclic lactam as a novel type of P2-P3 dipeptide surrogate. The synthesis and biological activity of this potent serine protease inhibitor is presented.
Flexible and convergent total synthesis of cyclotheonamide B
Bastiaans, Harold M.M.,Van der Baan, Juul L.,Ottenheijm, Harry C.J.
, p. 3880 - 3889 (2007/10/03)
A convergent approach using two key intermediates, segment A [a L-proline-L-α-hydroxy-β-homoarginine-D-phenylalamine (Pro-hArg-D-Phe) tripeptide] and segment B [a vinylogous L-tyrosine-L-2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was developed for the synthesis of cyclotheonamide B. The starting compound for the preparation of the hArg moiety 7, the predominant part of segment A, was N(α)-(benzyloxycarbonyl)-N(ω),N(ω)'-bis(tert-butyloxycarbonyl)-l-ar ginine methyl ester (15), which was converted into the aldehyde 16 and subsequently homologated using [tris(methylthio)methyl]lithium as a carboxylic acid anion equivalent. Coupling with properly protected Pro and D-Phe derivatives gave smoothly the desired Pro-hArg-D-Phe tripeptide derivative 24. The key feature of segment B, i.e., the L-tyrosine-derived α,β-unsaturated γ-amino acid 4, was prepared by a Wadsworth-Emmons olefination of the aldehyde 29 derived from N-(tert-butyloxycarbonyl), O-tert-butyl-L-tyrosine methyl ester (28). Selective N-(tert-butyloxycarbonyl) removal in the presence of the aryl tert-butyl ether present in the fully protected segment B, i.e., 32, was achieved by treatment with trimethylsilyl triflate/2,6-lutidine to give vTyr-Dpr dipeptide derivative 34 in quantitative yield. Coupling of the key intermediates 24 and 34 using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) afforded the protected linear pentapeptide 35 in high yield. Treatment of 35 with Pd(PPh3)4/morpholine resulted in simultaneous removal of the C-terminal allyl group and the N-terminal allyloxycarbonyl group to yield 36. Ring closure was effected under dilution conditions by treatment with TBTU/1-hydroxybenzotriazole/4-(dimethylamino)pyridine and gave the protected cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl group with Dess-Martin periodinane (24 h, 40°C) in the presence of tert-butyl alcohol gave 38, which was then subjected to O,N-deprotection with trifluoroacetic acid/thioanisole. Subsequent HPLC purification afforded cyclotheonamide B in an overall yield of 1.8% in 17 steps.
Total synthesis of cyclotheonamide B, a facile route towards analogues
Bastiaans, Harold M. M.,Van Der Baan, Juul L.,Ottenheijm, Harry C. J.
, p. 5963 - 5966 (2007/10/02)
A flexible, convergent synthesis of cyclotheonamide B (1b) was developed, starting from the constituent amino acids, using conventional benzyl-, t-butyl- and allyl-based protecting groups. By modification of the key intermediates, this approach allows the preparation of cyclotheonamide analogues.
