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Title: Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Abstract

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer’s disease.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [1];  [1];  [1];  [2];  [1]
+ Show Author Affiliations
  1. Bristol-Myers Squibb Company, Wallingford, CT (United States)
  2. Bristol-Myers Squibb Company, Princeton, NJ (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1352260
Resource Type:
Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 7; Journal Issue: 3; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; BACE1; inhibitor; aminothiazine; Aβ42; amyloid hypothesis; Alzheimer’s disease

Citation Formats

Wu, Yong-Jin, Guernon, Jason, Yang, Fukang, Snyder, Lawrence, Shi, Jianliang, Mcclure, Andrea, Rajamani, Ramkumar, Park, Hyunsoo, Ng, Alicia, Lewis, Hal, Chang, ChiehYing, Chang, ChiehYing, Toyn, Jeremy H., Toyn, Jeremy H., Albright, Charles F., Macor, John E., and Thompson, Lorin A. Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents. United States: N. p., 2016. Web. doi:10.1021/acsmedchemlett.5b00432.
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Wu, Yong-Jin, Guernon, Jason, Yang, Fukang, Snyder, Lawrence, Shi, Jianliang, Mcclure, Andrea, Rajamani, Ramkumar, Park, Hyunsoo, Ng, Alicia, Lewis, Hal, Chang, ChiehYing, Chang, ChiehYing, Toyn, Jeremy H., Toyn, Jeremy H., Albright, Charles F., Macor, John E., & Thompson, Lorin A. Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents. United States. https://doi.org/10.1021/acsmedchemlett.5b00432
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Wu, Yong-Jin, Guernon, Jason, Yang, Fukang, Snyder, Lawrence, Shi, Jianliang, Mcclure, Andrea, Rajamani, Ramkumar, Park, Hyunsoo, Ng, Alicia, Lewis, Hal, Chang, ChiehYing, Chang, ChiehYing, Toyn, Jeremy H., Toyn, Jeremy H., Albright, Charles F., Macor, John E., and Thompson, Lorin A. Thu . "Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents". United States. https://doi.org/10.1021/acsmedchemlett.5b00432. https://www.osti.gov/servlets/purl/1352260.
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@article{osti_1352260,
title = {Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents},
author = {Wu, Yong-Jin and Guernon, Jason and Yang, Fukang and Snyder, Lawrence and Shi, Jianliang and Mcclure, Andrea and Rajamani, Ramkumar and Park, Hyunsoo and Ng, Alicia and Lewis, Hal and Chang, ChiehYing and Chang, ChiehYing and Toyn, Jeremy H. and Toyn, Jeremy H. and Albright, Charles F. and Macor, John E. and Thompson, Lorin A.},
abstractNote = {By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose–response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer’s disease.},
doi = {10.1021/acsmedchemlett.5b00432},
journal = {ACS Medicinal Chemistry Letters},
number = 3,
volume = 7,
place = {United States},
year = {Thu Jan 21 00:00:00 EST 2016},
month = {Thu Jan 21 00:00:00 EST 2016}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acsmedchemlett.5b00432
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Citation Metrics:
Cited by: 27 works
Citation information provided by
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Figures / Tables:

Figure 1 Figure 1: Structure of 1 (LY2811376).
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Works referenced in this record:

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    • Mouchlis, Varnavas D.; Melagraki, Georgia; Zacharia, Lefteris C.
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    Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality
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    • Butler, Christopher R.; Ogilvie, Kevin; Martinez-Alsina, Luis
    • Journal of Medicinal Chemistry, Vol. 60, Issue 1
    • DOI: 10.1021/acs.jmedchem.6b01451

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