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Start Over Author "Audia JE" Journal bioorganic medicinal chemistry
2 results on '"Audia JE"'

1. Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.

Author

Winneroski LL, Erickson JA, Green SJ, Lopez JE, Stout SL, Porter WJ, Timm DE, Audia JE, Barberis M, Beck JP, Boggs LN, Borders AR, Boyer RD, Brier RA, Hembre EJ, Hendle J, Garcia-Losada P, Minguez JM, Mathes BM, May PC, Monk SA, Rankovic Z, Shi Y, Watson BM, Yang Z, and Mergott DJ

Subjects
Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Aspartic Acid Endopeptidases metabolism, Crystallography, X-Ray, Cyclopropanes chemical synthesis, Cyclopropanes chemistry, Dose-Response Relationship, Drug, Humans, Ligands, Models, Molecular, Molecular Conformation, Protease Inhibitors chemical synthesis, Protease Inhibitors chemistry, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Cyclopropanes pharmacology, Protease Inhibitors pharmacology
Abstract

Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Published
2020
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2. Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.

Author

Winneroski LL, Schiffler MA, Erickson JA, May PC, Monk SA, Timm DE, Audia JE, Beck JP, Boggs LN, Borders AR, Boyer RD, Brier RA, Hudziak KJ, Klimkowski VJ, Garcia Losada P, Mathes BM, Stout SL, Watson BM, and Mergott DJ

Subjects
Amyloid Precursor Protein Secretases chemistry, Amyloid Precursor Protein Secretases isolation & purification, Animals, Aspartic Acid Endopeptidases chemistry, Aspartic Acid Endopeptidases isolation & purification, Brain Chemistry, Bridged Bicyclo Compounds chemistry, Crystallography, X-Ray, Drug Design, Humans, Mice, Molecular Conformation, Molecular Docking Simulation, Protease Inhibitors chemistry, Stereoisomerism, Thiazines chemistry, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Bridged Bicyclo Compounds chemical synthesis, Protease Inhibitors chemical synthesis, Thiazines chemical synthesis
Abstract

The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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