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Your search keyword '"Machauer R"' showing total 3 results
Start Over Author "Machauer R" Topic drug discovery
3 results on '"Machauer R"'

1. Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer's Disease.

Author

Machauer R, Lueoend R, Hurth K, Veenstra SJ, Rueeger H, Voegtle M, Tintelnot-Blomley M, Rondeau JM, Jacobson LH, Laue G, Beltz K, and Neumann U

Subjects
Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Cell Line, Dogs, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Male, Mice, Mice, Inbred C57BL, Molecular Structure, Oxazines chemical synthesis, Oxazines chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Alzheimer Disease prevention & control, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Drug Discovery, Enzyme Inhibitors pharmacology, Oxazines pharmacology
Abstract

After identification of lead compound 6 , 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to 8 ( NB-360 ), an inhibitor with a p K a of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with NB-360 in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3 R ,6 R )-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2 H -[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 ( CNP520 , umibecestat ), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.

Published
2021
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2. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.

Author

Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, and Machauer R

Subjects
Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Dogs, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Madin Darby Canine Kidney Cells drug effects, Mice, Models, Molecular, Molecular Conformation, Oxazines chemical synthesis, Oxazines chemistry, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Drug Discovery, Enzyme Inhibitors pharmacology, Oxazines pharmacology
Abstract

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen., (Copyright © 2018. Published by Elsevier Ltd.)

Published
2018
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3. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides.

Author

Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Möbitz H, and Neumann U

Subjects
Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Peptides blood, Animals, Aspartic Acid Endopeptidases antagonists & inhibitors, Brain Chemistry, Crystallography, X-Ray, Cyclization, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Ethanolamines chemistry, Female, Inhibitory Concentration 50, Male, Mice, Molecular Structure, Rats, Structure-Activity Relationship, Substrate Specificity, Sulfoxides chemistry, Amyloid Precursor Protein Secretases drug effects, Amyloid beta-Peptides chemistry, Aspartic Acid Endopeptidases drug effects, Drug Discovery, Ethanolamines pharmacology, Sulfoxides pharmacology
Abstract

Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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