{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T08:58:32Z","timestamp":1777712312595,"version":"3.51.4"},"reference-count":35,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP16H05104"],"award-info":[{"award-number":["JP16H05104"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP25460160"],"award-info":[{"award-number":["JP25460160"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP25860093"],"award-info":[{"award-number":["JP25860093"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic &amp; Medicinal Chemistry"],"published-print":{"date-parts":[[2021,11]]},"DOI":"10.1016\/j.bmc.2021.116459","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T02:01:02Z","timestamp":1634608862000},"page":"116459","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":4,"special_numbering":"C","title":["Structure\u2013activity relationship study of hydroxyethylamine isostere and P1\u2032 site structure of peptide mimetic BACE1 inhibitors"],"prefix":"10.1016","volume":"50","author":[{"given":"Kazuya","family":"Kobayashi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Otani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saki","family":"Ijiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Kawasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Matsubara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Miyagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taishi","family":"Kitajima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Risa","family":"Iseki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuyasu","family":"Ishizawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoka","family":"Shindo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouta","family":"Okawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kouta","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syun","family":"Ando","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Momoka","family":"Kawakita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasunao","family":"Hattori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Akaji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmc.2021.116459_b0005","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1152\/physrev.2001.81.2.741","article-title":"Alzheimer\u2019s disease: Genes, proteins, and therapy","volume":"81","author":"Selkoe","year":"2001","journal-title":"Physiol Rev"},{"key":"10.1016\/j.bmc.2021.116459_b0010","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1056\/NEJMra0909142","article-title":"Alzheimer\u2019s disease","volume":"362","author":"Querfurth","year":"2010","journal-title":"N Engl J Med"},{"key":"10.1016\/j.bmc.2021.116459_b0015","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1126\/science.286.5440.735","article-title":"\u03b2-Secretase cleavage of Alzheimer\u2019s amyloid precursor protein by the transmembrane aspartic protease BACE","volume":"286","author":"Vassar","year":"1999","journal-title":"Science"},{"key":"10.1016\/j.bmc.2021.116459_b0020","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1006\/mcne.1999.0811","article-title":"Identification of a novel aspartic protease (Asp 2) as \u03b2-secretase","volume":"14","author":"Hussain","year":"1999","journal-title":"Mol Cell Neurosci"},{"key":"10.1016\/j.bmc.2021.116459_b0025","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1073\/pnas.97.4.1456","article-title":"Human aspartic protease memapsin 2 cleaves the \u03b2-secretase site of \u03b2-amyloid precursor protein","volume":"97","author":"Lin","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1016\/j.bmc.2021.116459_b0030","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1021\/jm101168r","article-title":"\u03b3-Secretase modulators as potential disease modifying anti-Alzheimer\u2019s drugs","volume":"54","author":"Oehlrich","year":"2011","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0035","doi-asserted-by":"crossref","first-page":"7389","DOI":"10.1021\/acs.jmedchem.5b01960","article-title":"Gamma secretase modulators: New Alzheimer\u2019s drugs on the horizon?","volume":"59","author":"Bursavich","year":"2016","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0040","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1474-4422(13)70276-X","article-title":"Targeting the \u03b2 secretase BACE1 for Alzheimer\u2019s disease therapy","volume":"13","author":"Yan","year":"2014","journal-title":"Lancet Neurol"},{"key":"10.1016\/j.bmc.2021.116459_b0045","doi-asserted-by":"crossref","first-page":"6735","DOI":"10.1039\/C3CS60460H","article-title":"BACE1 (\u03b2-secretase) inhibitors for the treatment of Alzheimer\u2019s disease","volume":"43","author":"Ghosh","year":"2014","journal-title":"Chem Soc Rev"},{"key":"10.1016\/j.bmc.2021.116459_b0050","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.bmcl.2014.11.087","article-title":"Structure-based design, synthesis and biological evaluation of novel \u03b2-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand","volume":"25","author":"Ghosh","year":"2015","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.bmc.2021.116459_b0055","doi-asserted-by":"crossref","first-page":"9807","DOI":"10.1021\/acs.jmedchem.7b01304","article-title":"Optimization of hydroxyethylamine transition state isosteres as aspartic protease inhibitors by exploiting conformational preferences","volume":"60","author":"Bueno","year":"2017","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0060","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3390\/molecules22010004","article-title":"Development and structural modification of BACE1 inhibitors","volume":"22","author":"Gu","year":"2017","journal-title":"Molecules"},{"key":"10.1016\/j.bmc.2021.116459_b0065","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.bmcl.2018.12.049","article-title":"New evolutions in the BACE1 inhibitor field from 2014 to 2018","volume":"29","author":"Hsiao","year":"2019","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.bmc.2021.116459_b0070","doi-asserted-by":"crossref","first-page":"103649","DOI":"10.1016\/j.bioorg.2020.103649","article-title":"Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands","volume":"97","author":"Iraji","year":"2020","journal-title":"Bioorg Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0075","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12929-017-0355-7","article-title":"Drug candidates in clinical trials for Alzheimer\u2019s disease","volume":"24","author":"Hung","year":"2017","journal-title":"J Biomed Sci"},{"key":"10.1016\/j.bmc.2021.116459_b0080","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.3233\/JAD-150834","article-title":"AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics","volume":"50","author":"Eketj\u00e4ll","year":"2016","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"10.1016\/j.bmc.2021.116459_b0085","first-page":"202","article-title":"Reversible and species-specific depigmentation effects of AZD3293, a BACE inhibitor for the treatment of Alzheimer's disease, are related to BACE2 inhibition and confined to epidermis and hair","volume":"3","author":"Cebers","year":"2016","journal-title":"J. Prev. Alzheimer\u2019s Dis."},{"key":"10.1016\/j.bmc.2021.116459_b0090","doi-asserted-by":"crossref","first-page":"10435","DOI":"10.1021\/acs.jmedchem.6b00307","article-title":"Discovery of the 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative verubecestat (MK-8931)\u2212A \u03b2-site amyloid precursor protein cleaving enzyme 1 inhibitor for the treatment of Alzheimer\u2019s disease","volume":"59","author":"Scott","year":"2016","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0095","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1706441","article-title":"Randomized trial of verubecestat for mild-to-moderate Alzheimer\u2019s disease","volume":"378","author":"Egan","year":"2018","journal-title":"N Engl J Med"},{"key":"10.1016\/j.bmc.2021.116459_b0100","unstructured":"Details of elenbecestat are given at the Alzforum website http:\/\/www.alzforum.org\/therapeutics\/elenbecestat (accessed July 24, 2021)."},{"key":"10.1016\/j.bmc.2021.116459_b0105","first-page":"202","article-title":"Profiling the dynamics of CSF and plasma A\u03b2 reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor","volume":"2","author":"Timmers","year":"2016","journal-title":"Alzheimers Dementia"},{"key":"10.1016\/j.bmc.2021.116459_b0110","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s13195-018-0415-6","article-title":"Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer\u2019s disease: randomized, double-blind, placebo-controlled study","volume":"10","author":"Timmers","year":"2018","journal-title":"Alzheimer\u2019s Res Ther"},{"key":"10.1016\/j.bmc.2021.116459_b0115","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1016\/j.bmc.2011.03.056","article-title":"Evaluation of superior BACE1 cleavage sequences containing unnatural amino acids","volume":"19","author":"Kakizawa","year":"2011","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0120","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1016\/j.bmcl.2006.01.108","article-title":"Design and synthesis of potent \u03b2-secretase (BACE1) inhibitors with P1\u2019 carboxylic acid bioisosteres","volume":"16","author":"Kimura","year":"2006","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.bmc.2021.116459_b0125","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.bmcl.2007.12.028","article-title":"Potent memapsin 2 (\u03b2-secretase) inhibitors: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation","volume":"18","author":"Ghosh","year":"2008","journal-title":"Bioorg Med Chem Lett"},{"key":"10.1016\/j.bmc.2021.116459_b0130","doi-asserted-by":"crossref","first-page":"5626","DOI":"10.1016\/j.bmc.2015.07.023","article-title":"Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors","volume":"23","author":"Hattori","year":"2015","journal-title":"Bioorg Med Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0135","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1021\/ja1071916","article-title":"Universal peptidomimetics","volume":"133","author":"Ko","year":"2011","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.bmc.2021.116459_b0140","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1002\/ejoc.200700515","article-title":"Highly selective synthesis of enantiopure (S, E)-\u03b1, \u03b2-unsaturated \u03b3-amino esters through a sequential reaction of ethyl dibromoacetate with \u03b1-amino aldehydes promoted by chromium dichloride","volume":"2007","author":"Concell\u00f3n","year":"2007","journal-title":"Eur J Org Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0145","doi-asserted-by":"crossref","first-page":"9450","DOI":"10.1021\/jo991065r","article-title":"Stereoselective intramolecular cyclization of allyl and homoallyl benzamide via \u03c0-allylpalladium complex catalyzed by Pd(0)","volume":"64","author":"Lee","year":"1999","journal-title":"J Org Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0150","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1016\/S0040-4020(02)00026-1","article-title":"Asymmetric induction in a new domino reaction of [3,3]-sigmatropic rearrangement of allylic thiocyanates and intramolecular heterocyclisation","volume":"58","author":"Gonda","year":"2002","journal-title":"Tetrahedron"},{"key":"10.1016\/j.bmc.2021.116459_b0155","doi-asserted-by":"crossref","first-page":"805","DOI":"10.3390\/molecules21060805","article-title":"Synthesis of chiral, enantiopure allylic amines by the Julia olefination of \u03b1-amino esters","volume":"21","author":"Benedetti","year":"2016","journal-title":"Molecules"},{"key":"10.1016\/j.bmc.2021.116459_b0160","doi-asserted-by":"crossref","first-page":"4755","DOI":"10.1021\/jo030063a","article-title":"Solid-phase synthesis of HTLV-1 protease inhibitors containing hydroxyethylamine dipeptide isostere","volume":"68","author":"Akaji","year":"2003","journal-title":"J Org Chem"},{"key":"10.1016\/j.bmc.2021.116459_b0165","unstructured":"The chemical shift of carbon signal [CH(OH)CH2NH] was detected by HSQC."},{"key":"10.1016\/j.bmc.2021.116459_b0170","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1021\/ol201828u","article-title":"Three-step synthesis of cyclopropyl peptidomimetics","volume":"13","author":"Dunlap","year":"2011","journal-title":"Org Lett"},{"key":"10.1016\/j.bmc.2021.116459_b0175","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1021\/cb500843r","article-title":"HIV protease inhibitors block streptolysin S production","volume":"10","author":"Maxson","year":"2015","journal-title":"ACS Chem Biol"}],"container-title":["Bioorganic &amp; Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089621004673?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089621004673?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T01:16:22Z","timestamp":1760836582000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0968089621004673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":35,"alternative-id":["S0968089621004673"],"URL":"https:\/\/doi.org\/10.1016\/j.bmc.2021.116459","relation":{},"ISSN":["0968-0896"],"issn-type":[{"value":"0968-0896","type":"print"}],"subject":[],"published":{"date-parts":[[2021,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Structure\u2013activity relationship study of hydroxyethylamine isostere and P1\u2032 site structure of peptide mimetic BACE1 inhibitors","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmc.2021.116459","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 Elsevier Ltd. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"116459"}}