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Your search keyword '"Diaz, Damaris"' showing total 4 results
Start Over Author "Diaz, Damaris" Topic amyloid precursor protein secretases
4 results on '"Diaz, Damaris"'

1. Potent benzoazepinone γ-secretase modulators with improved bioavailability.

Author

Methot JL, Fischer C, Li C, Rivkin A, Ahearn SP, Brown WC, Kattar S, Kelley E, Mampreian DM, Schell A, Rosenau A, Zhou H, Ball R, Deshmukh SV, Jeliazkova-Mecheva VV, Diaz D, Moy LY, Kenific CM, Moxham C, Shah S, Nuthall H, Szewczak AA, Hill A, Hughes B, Smotrov N, Munoz B, Miller TA, and Shearman MS

Subjects
Animals, Biological Availability, Mice, Mice, Transgenic, Rats, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases pharmacokinetics
Abstract

The triazolyl amide γ-secretase modulators are potent alternatives to the cinnamyl amides that have entered the clinic for the treatment of Alzheimer's disease. Herein we build on the lead benzoazepinones described in our prior communication with imidazomethoxyarene moiety alternatives that offer opportunities to fine tune physical properties as well as address hERG binding and PK. Both half-life and bioavailability were significantly improved, especially in dog, with robust brain Aβ42 lowering maintained in both transgenic mouse and rat., (Copyright © 2015. Published by Elsevier Ltd.)

Published
2015
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2. Discovery of novel triazolobenzazepinones as γ-secretase modulators with central Aβ42 lowering in rodents and rhesus monkeys.

Author

Fischer C, Zultanski SL, Zhou H, Methot JL, Shah S, Hayashi I, Hughes BL, Moxham CM, Bays NW, Smotrov N, Hill AD, Pan BS, Wu Z, Moy LY, Tanga F, Kenific C, Cruz JC, Walker D, Bouthillette M, Nikov GN, Deshmukh SV, Jeliazkova-Mecheva VV, Diaz D, Michener MS, Cook JJ, Munoz B, and Shearman MS

Subjects
Animals, Drug Discovery, Macaca mulatta, Mice, Mice, Transgenic, Rats, Rats, Sprague-Dawley, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism
Abstract

Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aβ42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aβ42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aβ42 levels., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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3. Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.

Author

Close J, Heidebrecht R Jr, Hendrix J, Li C, Munoz B, Surdi L, Kattar S, Tempest P, Moses P, Geng X, Hughes B, Smotrov N, Moxham C, Chapnick J, Kariv I, Nikov G, Burke JE, Deshmukh S, Jeliazkova-Mecheva V, Leach JK, Diaz D, Xu L, Yang Z, Kwei G, Moy L, Shah S, Tanga F, Kenefic C, Savage D, Shearman M, Ball RG, McNevin MJ, Markarewicz A, and Miller T

Subjects
Alzheimer Disease drug therapy, Amides pharmacology, Amyloid beta-Peptides biosynthesis, Animals, Brain drug effects, Brain metabolism, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Mice, Peptide Fragments biosynthesis, Amides chemical synthesis, Amyloid Precursor Protein Secretases antagonists & inhibitors, Enzyme Inhibitors chemistry, Piperidines chemistry
Abstract

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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4. Triazoles as γ-secretase modulators.

Author

Fischer C, Zultanski SL, Zhou H, Methot JL, Brown WC, Mampreian DM, Schell AJ, Shah S, Nuthall H, Hughes BL, Smotrov N, Kenific CM, Cruz JC, Walker D, Bouthillette M, Nikov GN, Savage DF, Jeliazkova-Mecheva VV, Diaz D, Szewczak AA, Bays N, Middleton RE, Munoz B, and Shearman MS

Subjects
Amyloid beta-Peptides metabolism, Animals, Enzyme Activation drug effects, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Inhibitory Concentration 50, Molecular Structure, Protein Binding, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Triazoles metabolism, Amyloid Precursor Protein Secretases metabolism, Triazoles chemical synthesis, Triazoles pharmacology
Abstract

Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aβ42 in Sprague-Dawley rats., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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