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Your search keyword '"Mattson, Matthew N."' showing total 3 results
Start Over Author "Mattson, Matthew N." Topic amyloid precursor protein secretases
3 results on '"Mattson, Matthew N."'

1. Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.

Author

Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW, Hom RK, Konradi AW, Marugg JL, Mattson MN, Neitzel ML, Semko CM, Sham HL, Smith J, Sun M, Truong AP, Ye XM, Xu YZ, Dappen MS, Jagodzinski JJ, Keim PS, Peterson B, Latimer LH, Quincy D, Wu J, Goldbach E, Ness DK, Quinn KP, Sauer JM, Wong K, Zhang H, Zmolek W, Brigham EF, Kholodenko D, Hu K, Kwong GT, Lee M, Liao A, Motter RN, Sacayon P, Santiago P, Willits C, Bard F, Bova MP, Hemphill SS, Nguyen L, Ruslim L, Tanaka K, Tanaka P, Wallace W, Yednock TA, and Basi GS

Subjects
Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Peptides cerebrospinal fluid, Amyloid beta-Peptides metabolism, Animals, Area Under Curve, Basic Helix-Loop-Helix Transcription Factors genetics, Dogs, Dose-Response Relationship, Drug, Drug Design, Drug Stability, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Gene Expression drug effects, Heterocyclic Compounds, 3-Ring chemistry, Homeodomain Proteins genetics, Humans, Male, Mice, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Models, Chemical, Molecular Structure, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Quinolines chemical synthesis, Quinolines pharmacokinetics, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Receptors, Notch metabolism, Structure-Activity Relationship, Sulfonamides chemistry, Time Factors, Transcription Factor HES-1, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Peptides antagonists & inhibitors, Enzyme Inhibitors pharmacology, Heterocyclic Compounds, 3-Ring pharmacology, Pyrazoles pharmacology, Quinolines pharmacology, Receptors, Notch antagonists & inhibitors, Sulfonamides pharmacology
Abstract

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.

Published
2013
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2. Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.

Author

Aubele DL, Truong AP, Dressen DB, Probst GD, Bowers S, Mattson MN, Semko CM, Sun M, Garofalo AW, Konradi AW, Sham HL, Zmolek W, Wong K, Goldbach E, Quinn KP, Sauer JM, Brigham EF, Wallace W, Nguyen L, Bova MP, Hemphill SS, and Basi G

Subjects
Amyloid beta-Peptides metabolism, Animals, Drug Evaluation, Preclinical, Enzyme Inhibitors chemistry, Heterocyclic Compounds, 3-Ring chemistry, Inhibitory Concentration 50, Mice, Mice, Inbred Strains, Structure-Activity Relationship, Sulfonamides chemistry, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Protein Precursor antagonists & inhibitors, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Heterocyclic Compounds, 3-Ring chemical synthesis, Heterocyclic Compounds, 3-Ring pharmacology, Sulfonamides chemical synthesis, Sulfonamides pharmacology
Abstract

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Published
2011
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3. Discovery of sulfonamide-pyrazole gamma-secretase inhibitors.

Author

Mattson MN, Neitzel ML, Quincy DA, Semko CM, Garofalo AW, Keim PS, Konradi AW, Pleiss MA, Sham HL, Brigham EF, Goldbach EG, Zhang H, Sauer JM, and Basi GS

Subjects
Animals, Crystallography, X-Ray, Humans, Inhibitory Concentration 50, Models, Molecular, Pyrazoles chemistry, Pyrazoles pharmacokinetics, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacokinetics, Alzheimer Disease drug therapy, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid Precursor Protein Secretases metabolism, Pyrazoles pharmacology, Sulfonamides pharmacology
Abstract

Utilizing a pharmacophore hypothesis, previously described gamma-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide-pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance., (2010 Elsevier Ltd. All rights reserved.)

Published
2010
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