- Identification and Profiling of Hydantoins - A Novel Class of Potent Antimycobacterial DprE1 Inhibitors
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Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein, we report the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-β-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity, and a good overall physicochemical profile. In addition, we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.
- Rogacki, Maciej K.,Pitta, Eleni,Balabon, Olga,Huss, Sophie,Lopez-Roman, Eva Maria,Argyrou, Argyrides,Blanco-Ruano, Delia,Cacho, Monica,Vande Velde, Christophe M. L.,Augustyns, Koen,Ballell, Lluis,Barros, David,Bates, Robert H.,Cunningham, Fraser,Van Der Veken, Pieter
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supporting information
p. 11221 - 11249
(2019/01/08)
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- 5-ARYL-1-IMINO-1-OXO-[1,2,4]THIADIAZINES
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The present invention provides a compound of formula I' having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are
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Page/Page column 42; 43
(2015/07/07)
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- 5-AMINO[1,4]THIAZINES AS BACE 1 INHIBITORS
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The present invention provides a compound of formula I having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.
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Page/Page column 33
(2014/01/07)
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- 1,4 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS
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The present invention relates to 1,4 Oxazines of formula (I): having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the pre
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Page/Page column 52-53
(2012/08/07)
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- Structure based design of iminohydantoin BACE1 inhibitors: Identification of an orally available, centrally active BACE1 inhibitor
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From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F′ subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound.
- Cumming, Jared N.,Smith, Elizabeth M.,Wang, Lingyan,Misiaszek, Jeffrey,Durkin, James,Pan, Jianping,Iserloh, Ulrich,Wu, Yusheng,Zhu, Zhaoning,Strickland, Corey,Voigt, Johannes,Chen, Xia,Kennedy, Matthew E.,Kuvelkar, Reshma,Hyde, Lynn A.,Cox, Kathleen,Favreau, Leonard,Czarniecki, Michael F.,Greenlee, William J.,McKittrick, Brian A.,Parker, Eric M.,Stamford, Andrew W.
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scheme or table
p. 2444 - 2449
(2012/05/19)
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- 1,4 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS
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The present invention relates to 1,4 Oxazines of formula I having BACE 1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the prese
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Page/Page column 29-30
(2012/07/28)
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- 1,4 OXAZINES AS BACE1 AND/OR BACE2 INHIBITORS
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The present invention provides 1,4 Oxazines of formula I having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present
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Page/Page column 35
(2012/08/08)
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- 3-AMINO-5-PHENYL-5,6-DIHYDRO-2H-[1,4]OXAZINES
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The present invention relates to 3-Amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines of formula I having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. T
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Page/Page column 29
(2011/04/14)
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- 3-AMINO-5-PHENYL-5,6-DIHYDRO-2H-[1,4]OXAZINE DERIVATIVES
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The present invention relates to 3-Amino-5-phenyl-5,6-dihydro-2H-[l,4]oxazine derivatives of formula (I) having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active
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Page/Page column 67
(2011/04/13)
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- Macrocyclic heterocyclic aspartyl protease inhibitors
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Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein U, W, X, L, Y, M, Z, c, d, e, f, g, h, s, t, R1, R2, R7, R8, R9/
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Page/Page column 14
(2010/11/25)
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