- Design and synthesis of bicyclic heterocycles as potent γ-secretase modulators
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The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
- Oehlrich, Daniel,Rombouts, Frederik J.R.,Berthelot, Didier,Bischoff, Francois P.,De Cleyn, Michel A.J.,Jaroskova, Libuse,MacDonald, Gregor,Mercken, Marc,Surkyn, Michel,Trabanco, Andres A.,Tresadern, Gary,Van Brandt, Sven,Velter, Adriana I.,Wu, Tongfei,Gijsen, Harrie J.M.
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p. 4794 - 4800
(2013/09/02)
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- Design and synthesis of dihydrobenzofuran amides as orally bioavailable, centrally active γ-secretase modulators
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We report the discovery and optimization of a novel series of dihydrobenzofuran amides as γ-secretase modulators (GSMs). Strategies for aligning in vitro potency with drug-like physicochemical properties and good microsomal stability while avoiding P-gp mediated efflux are discussed. Lead compounds such as 35 and 43 have moderate to good in vitro potency and excellent selectivity against Notch. Good oral bioavailability was achieved as well as robust brain Aβ42 lowering activity at 100 mg/kg po dose.
- Pettersson, Martin,Johnson, Douglas S.,Subramanyam, Chakrapani,Bales, Kelly R.,Am Ende, Christopher W.,Fish, Benjamin A.,Green, Michael E.,Kauffman, Gregory W.,Lira, Ricardo,Mullins, Patrick B.,Navaratnam, Thayalan,Sakya, Subas M.,Stiff, Cory M.,Tran, Tuan P.,Vetelino, Beth C.,Xie, Longfei,Zhang, Liming,Pustilnik, Leslie R.,Wood, Kathleen M.,O'Donnell, Christopher J.
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p. 2906 - 2911
(2012/06/04)
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- HETEROCYCLIC COMPOUND AND USE THEREOF
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The present invention provides a heterocycle derivative having a superior amyloid β production inhibitory activity and/or a superior γ-secretase modulation activity, and use thereof. A compound represented by the formula (I): wherein each symbol is as defined in the present specification, or a salt thereof.
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Page/Page column 52
(2012/03/26)
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- NOVEL SUBSTITUTED TRIAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted triazole derivatives of Formula (I) wherein Het1, R1, R2, A1, A2, A3, A4, L1, and L2 have the mean
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- NOVEL SUBSTITUTED BICYCLIC TRIAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted bicyclic triazole derivatives of Formula (I) wherein Het1, R1, R2, A1, A2, A3, A4, L1, and L2 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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- NOVEL SUBSTITUTED TRIAZOLE DERIVATIVES AS GAMMA SECRETASE MODULATORS
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The present invention is concerned with novel substituted triazole derivatives of Formula (I) wherein Het1, R1, R2, A1, A2, A3, A4, L1, and L2 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma sec
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- NOVEL PHENYL IMIDAZOLES AND PHENYL TRIAZOLES AS GAMMA-SECRETASE MODULATORS
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Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I) as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed
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Page/Page column 39
(2010/09/18)
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- PROCESS FOR PRODUCTION OF CINNAMAMIDE DERIVATIVE
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A compound (8) represented by the formula: (8) wherein R1 represents a 6- to 14-membered aromatic hydrocarbon ring group which may have a substituent; and n represents 0 to 2, can be produced with good efficiency by reacting a compound (3) represented by the formula: (3) wherein R1 and n are as defined above; and Q represents a single bond or -CH(Y)- where Y represents a hydrogen atom or a C1-6 alkyl group] with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the presence of a base.
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Page/Page column 62
(2008/12/07)
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