19989-67-4Relevant articles and documents
SPIRO-OXADIAZOLINE COMPOUNDS AS AGONISTS OF α-7-NICOTINIC ACETYLCHOLINE RECEPTORS
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Paragraph 00368-00369, (2015/05/19)
The present invention relates to novel spiro-oxadiazoline compounds that are suitable as agonists or partial agonists of a7-nAChR, and pharmaceutical compositions of the same, methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering a spiro-oxadiazoline cx7-nAChR agonist or partial agonist, to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
NONPEPTIDIC INHIBITORS OF CRUZAIN
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Page/Page column 49; 51, (2009/07/17)
Cruzain is the major cysteine protease of T. cruzi, which is the causative agent of Chagas' disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the Substrate Activity Screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor (38) was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored β-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl- oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group pTa, with 2,3,5,6-tetrafluorophenoxy methyl ketone (54) identified as one of the most potent inhibitors with a second order inactivation constant of 147,000 s-1M-1. This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemo therapeutics for Chagas' disease.
Identification of a new class of nonpeptidic inhibitors of cruzain
Brak, Katrien,Doyle, Patricia S.,McKerrow, James H.,Ellman, Jonathan A.
, p. 6404 - 6410 (2008/12/22)
Cruzain is the major cysteine protease of Trypanosoma cruzi, which is the causative agent of Chagas disease and is a promising target for the development of new chemotherapy. With the goal of developing potent nonpeptidic inhibitors of cruzain, the substrate activity screening (SAS) method was used to screen a library of protease substrates initially designed to target the homologous human protease cathepsin S. Structure-based design was next used to further improve substrate cleavage efficiency by introducing additional binding interactions in the S3 pocket of cruzain. The optimized substrates were then converted to inhibitors by the introduction of cysteine protease mechanism-based pharmacophores. Inhibitor 38 was determined to be reversible even though it incorporated the vinyl sulfone pharmacophore that is well documented to give irreversible cruzain inhibition for peptidic inhibitors. The previously unexplored β-chloro vinyl sulfone pharmacophore provided mechanistic insight that led to the development of potent irreversible acyl- and aryl-oxymethyl ketone cruzain inhibitors. For these inhibitors, potency did not solely depend on leaving group pKa, with 2,3,5,6- tetrafluorophenoxymethyl ketone 54 identified as one of the most potent inhibitors with a second-order inactivation constant of 147,000 s-1 M-1. This inhibitor completely eradicated the T. cruzi parasite from mammalian cell cultures and consequently has the potential to lead to new chemotherapeutics for Chagas disease.
AZOLIDINONE-VINYL FUSED-BENZENE DERIVATIVES
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Page 69, (2008/06/13)
The present invention is related to azolidinedione-vinyl fused-benzene derivatives of formula (I) for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries. Formula (I), wherein A, X, Y, Z, R1 , R2 and n are as described in the description.
ANABASEINE DERIVATIVES USEFUL IN THE TREATMENT OF NEURODEGENERATIVE DISEASES
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Page/Page column 80, (2008/06/13)
The compounds of the present invention are of formula (I): wherein A, R3, R4 is as defined herein, are useful as ligands for nicotinic receptors.
