Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality
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 dono...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-01, Vol.60 (1), p.386-402 |
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| creator | Butler, Christopher R Ogilvie, Kevin Martinez-Alsina, Luis Barreiro, Gabriela Beck, Elizabeth M Nolan, Charles E Atchison, Kevin Benvenuti, Eric Buzon, Leanne Doran, Shawn Gonzales, Cathleen Helal, Christopher J Hou, Xinjun Hsu, Mei-Hui Johnson, Eric F Lapham, Kimberly Lanyon, Lorraine Parris, Kevin O’Neill, Brian T Riddell, David Robshaw, Ashley Vajdos, Felix Brodney, Michael A |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.6b01451 |
| format | Article |
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Stanford Synchrotron Radiation Lightsource (SSRL)</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Amines</subject><subject>Amino Acid Sequence</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Amyloid Precursor Protein Secretases - chemistry</subject><subject>Anilides - chemistry</subject><subject>Animals</subject><subject>Brain - metabolism</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Crystallization</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glycine - chemistry</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Male</subject><subject>Mice</subject><subject>Patch-Clamp Techniques</subject><subject>Selectivity</subject><subject>Structure-Activity Relationship</subject><subject>Substituents</subject><subject>Tandem Mass Spectrometry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS0EotvCN0DI4tQesnjsxEk4VNou21KpEgfgbDnOZOMqsYvtFO23J8tuK7hwmsO89-bPj5B3wJbAOHzUJi7vR2xNj-NSNgzyAl6QBRScZXnF8pdkwRjnGZdcnJDTGO8ZYwK4eE1OeFnXJZR8Qbar0To_Yup3Q_YZg33Ell5h0vQbmjDXiPT8arXewAW9db1tbPIhfqIbt9Vb67b0Zthxwegvm3o_JaodXTk72Bbp9eRMst7pwabdG_Kq00PEt8d6Rn5cb76vv2R3X29u16u7TOelTBnoWgIYyTs-L9tUjZYNIFa8bqHBXJRGmkpUsi0qXrKuzltRV2CKvAMAWXfijFwech-mZv8cdCnoQT0EO-qwU15b9W_H2V5t_aMqcgk1F3PAh0OAj8mqaGxC0xvvHJqkoGCyEHIWnR-nBP9zwpjUaKPBYdAO_RQVVAUIJmq5z8sPUhN8jAG7512AqT1INYNUTyDVEeRse__3Hc-mJ3KzgB0Ef-x-CvOf4_8zfwOPu6yO</recordid><startdate>20170112</startdate><enddate>20170112</enddate><creator>Butler, Christopher R</creator><creator>Ogilvie, Kevin</creator><creator>Martinez-Alsina, Luis</creator><creator>Barreiro, Gabriela</creator><creator>Beck, Elizabeth M</creator><creator>Nolan, Charles E</creator><creator>Atchison, Kevin</creator><creator>Benvenuti, Eric</creator><creator>Buzon, Leanne</creator><creator>Doran, Shawn</creator><creator>Gonzales, Cathleen</creator><creator>Helal, Christopher J</creator><creator>Hou, Xinjun</creator><creator>Hsu, Mei-Hui</creator><creator>Johnson, Eric F</creator><creator>Lapham, Kimberly</creator><creator>Lanyon, Lorraine</creator><creator>Parris, Kevin</creator><creator>O’Neill, Brian T</creator><creator>Riddell, David</creator><creator>Robshaw, Ashley</creator><creator>Vajdos, Felix</creator><creator>Brodney, Michael A</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9387-5011</orcidid><orcidid>https://orcid.org/0000000293875011</orcidid></search><sort><creationdate>20170112</creationdate><title>Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality</title><author>Butler, Christopher R ; Ogilvie, Kevin ; Martinez-Alsina, Luis ; Barreiro, Gabriela ; Beck, Elizabeth M ; Nolan, Charles E ; Atchison, Kevin ; Benvenuti, Eric ; Buzon, Leanne ; Doran, Shawn ; Gonzales, Cathleen ; Helal, Christopher J ; Hou, Xinjun ; Hsu, Mei-Hui ; Johnson, Eric F ; Lapham, Kimberly ; Lanyon, Lorraine ; Parris, Kevin ; O’Neill, Brian T ; Riddell, David ; Robshaw, Ashley ; Vajdos, Felix ; Brodney, Michael A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a476t-1a9611c62f2003b8ba6b1ee829d1be437c6c8386d58270f94d3981c54f11169f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amines</topic><topic>Amino Acid Sequence</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Amyloid Precursor Protein Secretases - chemistry</topic><topic>Anilides - chemistry</topic><topic>Animals</topic><topic>Brain - metabolism</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Crystallization</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glycine - chemistry</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</topic><topic>Male</topic><topic>Mice</topic><topic>Patch-Clamp Techniques</topic><topic>Selectivity</topic><topic>Structure-Activity Relationship</topic><topic>Substituents</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Butler, Christopher R</creatorcontrib><creatorcontrib>Ogilvie, Kevin</creatorcontrib><creatorcontrib>Martinez-Alsina, Luis</creatorcontrib><creatorcontrib>Barreiro, Gabriela</creatorcontrib><creatorcontrib>Beck, Elizabeth M</creatorcontrib><creatorcontrib>Nolan, Charles E</creatorcontrib><creatorcontrib>Atchison, Kevin</creatorcontrib><creatorcontrib>Benvenuti, Eric</creatorcontrib><creatorcontrib>Buzon, Leanne</creatorcontrib><creatorcontrib>Doran, Shawn</creatorcontrib><creatorcontrib>Gonzales, Cathleen</creatorcontrib><creatorcontrib>Helal, Christopher J</creatorcontrib><creatorcontrib>Hou, Xinjun</creatorcontrib><creatorcontrib>Hsu, Mei-Hui</creatorcontrib><creatorcontrib>Johnson, Eric F</creatorcontrib><creatorcontrib>Lapham, Kimberly</creatorcontrib><creatorcontrib>Lanyon, Lorraine</creatorcontrib><creatorcontrib>Parris, Kevin</creatorcontrib><creatorcontrib>O’Neill, Brian T</creatorcontrib><creatorcontrib>Riddell, David</creatorcontrib><creatorcontrib>Robshaw, Ashley</creatorcontrib><creatorcontrib>Vajdos, Felix</creatorcontrib><creatorcontrib>Brodney, Michael A</creatorcontrib><creatorcontrib>SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)</creatorcontrib><creatorcontrib>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Butler, Christopher R</au><au>Ogilvie, Kevin</au><au>Martinez-Alsina, Luis</au><au>Barreiro, Gabriela</au><au>Beck, Elizabeth M</au><au>Nolan, Charles E</au><au>Atchison, Kevin</au><au>Benvenuti, Eric</au><au>Buzon, Leanne</au><au>Doran, Shawn</au><au>Gonzales, Cathleen</au><au>Helal, Christopher J</au><au>Hou, Xinjun</au><au>Hsu, Mei-Hui</au><au>Johnson, Eric F</au><au>Lapham, Kimberly</au><au>Lanyon, Lorraine</au><au>Parris, Kevin</au><au>O’Neill, Brian T</au><au>Riddell, David</au><au>Robshaw, Ashley</au><au>Vajdos, Felix</au><au>Brodney, Michael A</au><aucorp>SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)</aucorp><aucorp>Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-01-12</date><risdate>2017</risdate><volume>60</volume><issue>1</issue><spage>386</spage><epage>402</epage><pages>386-402</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>27997172</pmid><doi>10.1021/acs.jmedchem.6b01451</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-9387-5011</orcidid><orcidid>https://orcid.org/0000000293875011</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2017-01, Vol.60 (1), p.386-402 |
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| source | MEDLINE; American Chemical Society (ACS) Journals |
| subjects | Amines Amino Acid Sequence Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - chemistry Anilides - chemistry Animals Brain - metabolism Chromatography, High Pressure Liquid Crystallization Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Glycine - chemistry Inhibition Inhibitors INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Male Mice Patch-Clamp Techniques Selectivity Structure-Activity Relationship Substituents Tandem Mass Spectrometry |
| title | Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality |
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