The Experts below are selected from a list of 1209 Experts worldwide ranked by ideXlab platform

Shawn D Doran - One of the best experts on this subject based on the ideXlab platform.

  • aminomethyl derived beta secretase bace1 inhibitors engaging gly230 without an Anilide functionality
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Christopher Ryan Butler, Kevin Ogilvie, Luis Martinezalsina, Gabriela Barreiro, Elizabeth Mary Beck, Charles E Nolan, Kevin Atchison, Eric Benvenuti, Leanne M Buzon, Shawn D Doran
    Abstract:

    A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an Anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the Anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

Christopher Ryan Butler - One of the best experts on this subject based on the ideXlab platform.

  • aminomethyl derived beta secretase bace1 inhibitors engaging gly230 without an Anilide functionality
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Christopher Ryan Butler, Kevin Ogilvie, Luis Martinezalsina, Gabriela Barreiro, Elizabeth Mary Beck, Charles E Nolan, Kevin Atchison, Eric Benvenuti, Leanne M Buzon, Shawn D Doran
    Abstract:

    A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an Anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the Anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

  • Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality
    2016
    Co-Authors: Christopher Ryan Butler, Kevin Ogilvie, Gabriela Barreiro, Elizabeth Mary Beck, Charles E Nolan, Kevin Atchison, Eric Benvenuti, Leanne M Buzon, Luis Martinez-alsina, Shawn Doran
    Abstract:

    A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an Anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the Anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor

Yves Janin - One of the best experts on this subject based on the ideXlab platform.

  • On the Knorr synthesis of 6-bromo-4-methylquinolin-2(1H)-one
    SYNTHESIS, 2011
    Co-Authors: Nicolas Wlodarczyk, Catherine Simenel, Muriel Delepierre, Jean-christophe Barale, Yves Janin
    Abstract:

    In the course of our work on infectious diseases, we were led to prepare 6-bromo-2-chloro-4-methylquinoline as a starting material. Since surprisingly little has been reported in the literature, the two synthetic steps to this compound were investigated. The synthesis involves a condensation between -ketoesters and 4-bromoaniline and the cyclization of the resulting Anilides into 6-bromoquinolin-2(1H)-one otherwise known as the Knorr reaction. The 1H NMR monitoring of the first step allowed us to optimize the conditions leading specifically to the Anilide without the occurrence of the alternative crotonate. To illustrate the scope of our finding, few additional Anilides featuring electron attracting groups were prepared. The study of their cyclization revealed some unsuspected steric effect governing this second step. Aside from rectifying few claims in this chemistry, this study led to a three-step preparation of 6-bromo-2-chloro-4-methylquinoline in a 48 % overall yield from 4-bromoaniline.

Jin-pei Cheng - One of the best experts on this subject based on the ideXlab platform.

  • atroposelective catalytic asymmetric allylic alkylation reaction for axially chiral Anilides with achiral morita baylis hillman carbonates
    Journal of the American Chemical Society, 2018
    Co-Authors: Shoulei Li, Chen Yang, Han-liang Zheng, Quan Wu, Xin Li, Jin-pei Cheng
    Abstract:

    A highly efficient method to access axially chiral Anilides through asymmetric allylic alkylation reaction with achiral Morita–Baylis–Hillman carbonates by using a biscinchona alkaloid catalyst was reported. Through the atroposelective approach, a broad range of axially chiral Anilide products with different acyl groups, such as substituted phenyl, naphthyl, alkyl, enyl, styryl, and benzyl, were generated with very good yields, moderate to excellent cis:trans ratios, and good to excellent enantioselectivities. The reaction can be scaled up, and the synthetic utility of axially chiral Anilides was proved by transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction.

  • Atroposelective Catalytic Asymmetric Allylic Alkylation Reaction for Axially Chiral Anilides with Achiral Morita–Baylis–Hillman Carbonates
    2018
    Co-Authors: Chen Yang, Han-liang Zheng, Jin-pei Cheng
    Abstract:

    A highly efficient method to access axially chiral Anilides through asymmetric allylic alkylation reaction with achiral Morita–Baylis–Hillman carbonates by using a biscinchona alkaloid catalyst was reported. Through the atroposelective approach, a broad range of axially chiral Anilide products with different acyl groups, such as substituted phenyl, naphthyl, alkyl, enyl, styryl, and benzyl, were generated with very good yields, moderate to excellent cis:trans ratios, and good to excellent enantioselectivities. The reaction can be scaled up, and the synthetic utility of axially chiral Anilides was proved by transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction

Gabriela Barreiro - One of the best experts on this subject based on the ideXlab platform.

  • aminomethyl derived beta secretase bace1 inhibitors engaging gly230 without an Anilide functionality
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Christopher Ryan Butler, Kevin Ogilvie, Luis Martinezalsina, Gabriela Barreiro, Elizabeth Mary Beck, Charles E Nolan, Kevin Atchison, Eric Benvenuti, Leanne M Buzon, Shawn D Doran
    Abstract:

    A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an Anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the Anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

  • Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality
    2016
    Co-Authors: Christopher Ryan Butler, Kevin Ogilvie, Gabriela Barreiro, Elizabeth Mary Beck, Charles E Nolan, Kevin Atchison, Eric Benvenuti, Leanne M Buzon, Luis Martinez-alsina, Shawn Doran
    Abstract:

    A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an Anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the Anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug–drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor