Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and comp...

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Veröffentlicht in:ChemMedChem 2017-12, Vol.12 (23), p.1977-1984
Hauptverfasser: Gu, Xingxian, Gupta, Vijayalaxmi, Yang, Yan, Zhu, Jin‐Yi, Carlson, Erick J., Kingsley, Carolyn, Tash, Joseph S., Schönbrunn, Ernst, Hawkinson, Jon, Georg, Gunda I.
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container_end_page 1984
container_issue 23
container_start_page 1977
container_title ChemMedChem
container_volume 12
creator Gu, Xingxian
Gupta, Vijayalaxmi
Yang, Yan
Zhu, Jin‐Yi
Carlson, Erick J.
Kingsley, Carolyn
Tash, Joseph S.
Schönbrunn, Ernst
Hawkinson, Jon
Georg, Gunda I.
description Analogues of N‐butyl‐1‐deoxynojirimycin (NB‐DNJ) were prepared and assayed for inhibition of ceramide‐specific glucosyltransferase (CGT), non‐lysosomal β‐glucosidase 2 (GBA2) and the lysosomal β‐glucosidase 1 (GBA1). Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (>1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development. β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.
doi_str_mv 10.1002/cmdc.201700558
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Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (&gt;1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development. β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201700558</identifier><identifier>PMID: 28975712</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>1-Deoxynojirimycin - analogs &amp; derivatives ; 1-Deoxynojirimycin - chemistry ; 1-Deoxynojirimycin - pharmacology ; Amino Alcohols - chemistry ; Amino Alcohols - pharmacology ; aminocyclitols ; Analogs ; beta-Glucosidase - antagonists &amp; inhibitors ; beta-Glucosidase - metabolism ; Ceramide ; Cyclopentane ; Cyclopentanes - chemistry ; Cyclopentanes - pharmacology ; Dose-Response Relationship, Drug ; Drug Discovery ; enzyme inhibition ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Glucosyltransferase ; Humans ; Inhibition ; Inhibitors ; lysosomal glucosidase 1 ; Molecular Conformation ; N-butyl-1-deoxynojirimycin ; Nitrogen ; non-lysosomal glucosidase 2 ; Stereochemistry ; Structure-Activity Relationship ; Substitutes</subject><ispartof>ChemMedChem, 2017-12, Vol.12 (23), p.1977-1984</ispartof><rights>2017 The Authors. Published by Wiley-VCH Verlag GmbH &amp; Co. KGaA.</rights><rights>2017 Wiley-VCH Verlag GmbH &amp; Co. 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Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (&gt;1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development. β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.</description><subject>1-Deoxynojirimycin - analogs &amp; derivatives</subject><subject>1-Deoxynojirimycin - chemistry</subject><subject>1-Deoxynojirimycin - pharmacology</subject><subject>Amino Alcohols - chemistry</subject><subject>Amino Alcohols - pharmacology</subject><subject>aminocyclitols</subject><subject>Analogs</subject><subject>beta-Glucosidase - antagonists &amp; inhibitors</subject><subject>beta-Glucosidase - metabolism</subject><subject>Ceramide</subject><subject>Cyclopentane</subject><subject>Cyclopentanes - chemistry</subject><subject>Cyclopentanes - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>enzyme inhibition</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Glucosyltransferase</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>lysosomal glucosidase 1</subject><subject>Molecular Conformation</subject><subject>N-butyl-1-deoxynojirimycin</subject><subject>Nitrogen</subject><subject>non-lysosomal glucosidase 2</subject><subject>Stereochemistry</subject><subject>Structure-Activity Relationship</subject><subject>Substitutes</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNqFUcGO0zAQtRCIXRauHJElLnBosZ04tjkgpS0si5aCVDhbjuPsukrjYjuF3PYTkPgI_mu_BGe7FDhxsGY08-bN-D0AHmM0xQiRF3pT6ylBmCFEKb8DjjEv0IRhzu4eciaOwIMQ1gjlOcf8PjgiXDDKMDkGP1fR9zr23lxf_Sh1tDsbB7iKfW1NgK6By-ur77M-Dm2KOL3auG9D59bW282gbQefLWepvFi-ew7LTrXuojfhJVzYoN3O-GHk-Oii6SJUXQ1XpjXjFgPLje2cHnTrtqlpo2vhWXdpq5T5m82nsxLfzKSEPAT3GtUG8-g2noDPb15_mr-dnH84PZuX5xOdF5xPMi40UpjmOaMUacZoXTUGCdIowkST6cbkNcK4yQXPVSMwyhjNisokCYuiqrIT8GrPu-2rjal1Os2rVm7Tb5UfpFNW_tvp7KW8cDtJGUmKokTw9JbAuy9JiijXrvdJmCCxYBkRBRUjarpHae9C8KY5bMBIjsbK0Vh5MDYNPPn7rgP8t5MJIPaAr7Y1w3_o5Pz9Yv6H_BevZLaV</recordid><startdate>20171207</startdate><enddate>20171207</enddate><creator>Gu, Xingxian</creator><creator>Gupta, Vijayalaxmi</creator><creator>Yang, Yan</creator><creator>Zhu, Jin‐Yi</creator><creator>Carlson, Erick J.</creator><creator>Kingsley, Carolyn</creator><creator>Tash, Joseph S.</creator><creator>Schönbrunn, Ernst</creator><creator>Hawkinson, Jon</creator><creator>Georg, Gunda I.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><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>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0288-384X</orcidid><orcidid>https://orcid.org/0000-0001-5461-7071</orcidid><orcidid>https://orcid.org/0000-0001-8564-7345</orcidid><orcidid>https://orcid.org/0000-0001-9074-1571</orcidid><orcidid>https://orcid.org/0000-0001-5407-7458</orcidid><orcidid>https://orcid.org/0000-0001-8915-3393</orcidid><orcidid>https://orcid.org/0000-0001-5436-4262</orcidid><orcidid>https://orcid.org/0000-0002-3589-3510</orcidid><orcidid>https://orcid.org/0000-0002-8900-9460</orcidid><orcidid>https://orcid.org/0000-0002-9514-727X</orcidid></search><sort><creationdate>20171207</creationdate><title>Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2</title><author>Gu, Xingxian ; Gupta, Vijayalaxmi ; Yang, Yan ; Zhu, Jin‐Yi ; Carlson, Erick J. ; Kingsley, Carolyn ; Tash, Joseph S. ; Schönbrunn, Ernst ; Hawkinson, Jon ; Georg, Gunda I.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4688-389c0a15447550c775dbfe092fa279f3cfe4d011f4984af91037536be20166bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>1-Deoxynojirimycin - analogs &amp; derivatives</topic><topic>1-Deoxynojirimycin - chemistry</topic><topic>1-Deoxynojirimycin - pharmacology</topic><topic>Amino Alcohols - chemistry</topic><topic>Amino Alcohols - pharmacology</topic><topic>aminocyclitols</topic><topic>Analogs</topic><topic>beta-Glucosidase - antagonists &amp; inhibitors</topic><topic>beta-Glucosidase - metabolism</topic><topic>Ceramide</topic><topic>Cyclopentane</topic><topic>Cyclopentanes - chemistry</topic><topic>Cyclopentanes - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>enzyme inhibition</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Glucosyltransferase</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>lysosomal glucosidase 1</topic><topic>Molecular Conformation</topic><topic>N-butyl-1-deoxynojirimycin</topic><topic>Nitrogen</topic><topic>non-lysosomal glucosidase 2</topic><topic>Stereochemistry</topic><topic>Structure-Activity Relationship</topic><topic>Substitutes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gu, Xingxian</creatorcontrib><creatorcontrib>Gupta, Vijayalaxmi</creatorcontrib><creatorcontrib>Yang, Yan</creatorcontrib><creatorcontrib>Zhu, Jin‐Yi</creatorcontrib><creatorcontrib>Carlson, Erick J.</creatorcontrib><creatorcontrib>Kingsley, Carolyn</creatorcontrib><creatorcontrib>Tash, Joseph S.</creatorcontrib><creatorcontrib>Schönbrunn, Ernst</creatorcontrib><creatorcontrib>Hawkinson, Jon</creatorcontrib><creatorcontrib>Georg, Gunda I.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health &amp; 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Compounds 5 a–6 f, which carry sterically demanding nitrogen substituents, and compound 13, devoid of the C3 and C5 hydroxy groups present in DNJ/NB‐DGJ (N‐butyldeoxygalactojirimycin) showed no inhibitory activity for CGT or GBA2. Inversion of stereochemistry at C4 of N‐(n‐butyl)‐ and N‐(n‐nonyl)‐DGJ (compounds 24) also led to a loss of activity in these assays. The aminocyclopentitols N‐(n‐butyl)‐ (35 a), N‐(n‐nonyl)‐4‐amino‐5‐(hydroxymethyl)cyclopentane‐ (35 b), and N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl)‐1,2,3‐triol (35 f), were found to be selective inhibitors of GBA1 and GBA2 that did not inhibit CGT (&gt;1 mm), with the exception of 35 f, which inhibited CGT with an IC50 value of 1 mm. The N‐butyl analogue 35 a was 100‐fold selective for inhibiting GBA1 over GBA2 (Ki values of 32 nm and 3.3 μm for GBA1 and GBA2, respectively). The N‐nonyl analogue 35 b displayed a Ki value of ≪14 nm for GBA1 inhibition and a Ki of 43 nm for GBA2. The N‐(1‐(pentyloxy)methyl)adamantan‐1‐yl) derivative 35 f had Ki values of ≈16 and 14 nm for GBA1 and GBA2, respectively. The related N‐bis‐substituted aminocyclopentitols were found to be significantly less potent inhibitors than their mono‐substituted analogues. The aminocyclopentitol scaffold should hold promise for further inhibitor development. β‐Glucosidase‐selective inhibitors: Aminocyclopentitols were prepared and assayed for inhibition of carbohydrate‐processing enzymes, including CGT, GBA1, and GBA2. N‐Butylaminocyclopentitol was found to be a potent and selective inhibitor of GBA1. The N‐nonyl and N‐1‐((pentyloxy)methyl)adamantan‐1‐yl analogues potently inhibited both GBA1 (Ki≪14 nm, and Ki≤16, respectively) and GBA2 (Ki≪43 nm, and Ki=14 nm, respectively). The butyl and nonyl analogues did not inhibit CGT at 1 mm, and the Ki value for the adamantyl analogue was 1 mm. The N‐alkylaminocyclopentitols hold promise for future inhibitor development.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28975712</pmid><doi>10.1002/cmdc.201700558</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-0288-384X</orcidid><orcidid>https://orcid.org/0000-0001-5461-7071</orcidid><orcidid>https://orcid.org/0000-0001-8564-7345</orcidid><orcidid>https://orcid.org/0000-0001-9074-1571</orcidid><orcidid>https://orcid.org/0000-0001-5407-7458</orcidid><orcidid>https://orcid.org/0000-0001-8915-3393</orcidid><orcidid>https://orcid.org/0000-0001-5436-4262</orcidid><orcidid>https://orcid.org/0000-0002-3589-3510</orcidid><orcidid>https://orcid.org/0000-0002-8900-9460</orcidid><orcidid>https://orcid.org/0000-0002-9514-727X</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1860-7179
ispartof ChemMedChem, 2017-12, Vol.12 (23), p.1977-1984
issn 1860-7179
1860-7187
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5725710
source MEDLINE; Wiley Blackwell Journals
subjects 1-Deoxynojirimycin - analogs & derivatives
1-Deoxynojirimycin - chemistry
1-Deoxynojirimycin - pharmacology
Amino Alcohols - chemistry
Amino Alcohols - pharmacology
aminocyclitols
Analogs
beta-Glucosidase - antagonists & inhibitors
beta-Glucosidase - metabolism
Ceramide
Cyclopentane
Cyclopentanes - chemistry
Cyclopentanes - pharmacology
Dose-Response Relationship, Drug
Drug Discovery
enzyme inhibition
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Glucosyltransferase
Humans
Inhibition
Inhibitors
lysosomal glucosidase 1
Molecular Conformation
N-butyl-1-deoxynojirimycin
Nitrogen
non-lysosomal glucosidase 2
Stereochemistry
Structure-Activity Relationship
Substitutes
title Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2
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