Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481

[Image: see text] A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ(1–42) and Aβ(1–40) in the plas...

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Autores principales: Boy, Kenneth M., Guernon, Jason M., Zuev, Dmitry S., Xu, Li, Zhang, Yunhui, Shi, Jianliang, Marcin, Lawrence R., Higgins, Mendi A., Wu, Yong-Jin, Krishnananthan, Subramaniam, Li, Jianqing, Trehan, Ashok, Smith, Daniel, Toyn, Jeremy H., Meredith, Jere E., Burton, Catherine R., Kimura, S. Roy, Zvyaga, Tatyana, Zhuo, Xiaoliang, Lentz, Kimberley A., Grace, James E., Denton, Rex, Morrison, John S., Mathur, Arvind, Albright, Charles F., Ahlijanian, Michael K., Olson, Richard E., Thompson, Lorin A., Macor, John E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421538/
https://www.ncbi.nlm.nih.gov/pubmed/30891132
http://dx.doi.org/10.1021/acsmedchemlett.8b00541
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author Boy, Kenneth M.
Guernon, Jason M.
Zuev, Dmitry S.
Xu, Li
Zhang, Yunhui
Shi, Jianliang
Marcin, Lawrence R.
Higgins, Mendi A.
Wu, Yong-Jin
Krishnananthan, Subramaniam
Li, Jianqing
Trehan, Ashok
Smith, Daniel
Toyn, Jeremy H.
Meredith, Jere E.
Burton, Catherine R.
Kimura, S. Roy
Zvyaga, Tatyana
Zhuo, Xiaoliang
Lentz, Kimberley A.
Grace, James E.
Denton, Rex
Morrison, John S.
Mathur, Arvind
Albright, Charles F.
Ahlijanian, Michael K.
Olson, Richard E.
Thompson, Lorin A.
Macor, John E.
author_facet Boy, Kenneth M.
Guernon, Jason M.
Zuev, Dmitry S.
Xu, Li
Zhang, Yunhui
Shi, Jianliang
Marcin, Lawrence R.
Higgins, Mendi A.
Wu, Yong-Jin
Krishnananthan, Subramaniam
Li, Jianqing
Trehan, Ashok
Smith, Daniel
Toyn, Jeremy H.
Meredith, Jere E.
Burton, Catherine R.
Kimura, S. Roy
Zvyaga, Tatyana
Zhuo, Xiaoliang
Lentz, Kimberley A.
Grace, James E.
Denton, Rex
Morrison, John S.
Mathur, Arvind
Albright, Charles F.
Ahlijanian, Michael K.
Olson, Richard E.
Thompson, Lorin A.
Macor, John E.
author_sort Boy, Kenneth M.
collection PubMed
description [Image: see text] A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ(1–42) and Aβ(1–40) in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ(1–37) and Aβ(1–38) were observed, with no change in the total amount of Aβ(1–x) produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.
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spelling pubmed-64215382019-03-19 Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481 Boy, Kenneth M. Guernon, Jason M. Zuev, Dmitry S. Xu, Li Zhang, Yunhui Shi, Jianliang Marcin, Lawrence R. Higgins, Mendi A. Wu, Yong-Jin Krishnananthan, Subramaniam Li, Jianqing Trehan, Ashok Smith, Daniel Toyn, Jeremy H. Meredith, Jere E. Burton, Catherine R. Kimura, S. Roy Zvyaga, Tatyana Zhuo, Xiaoliang Lentz, Kimberley A. Grace, James E. Denton, Rex Morrison, John S. Mathur, Arvind Albright, Charles F. Ahlijanian, Michael K. Olson, Richard E. Thompson, Lorin A. Macor, John E. ACS Med Chem Lett [Image: see text] A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aβ(1–42) and Aβ(1–40) in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aβ(1–37) and Aβ(1–38) were observed, with no change in the total amount of Aβ(1–x) produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials. American Chemical Society 2019-02-17 /pmc/articles/PMC6421538/ /pubmed/30891132 http://dx.doi.org/10.1021/acsmedchemlett.8b00541 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Boy, Kenneth M.
Guernon, Jason M.
Zuev, Dmitry S.
Xu, Li
Zhang, Yunhui
Shi, Jianliang
Marcin, Lawrence R.
Higgins, Mendi A.
Wu, Yong-Jin
Krishnananthan, Subramaniam
Li, Jianqing
Trehan, Ashok
Smith, Daniel
Toyn, Jeremy H.
Meredith, Jere E.
Burton, Catherine R.
Kimura, S. Roy
Zvyaga, Tatyana
Zhuo, Xiaoliang
Lentz, Kimberley A.
Grace, James E.
Denton, Rex
Morrison, John S.
Mathur, Arvind
Albright, Charles F.
Ahlijanian, Michael K.
Olson, Richard E.
Thompson, Lorin A.
Macor, John E.
Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
title Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
title_full Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
title_fullStr Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
title_full_unstemmed Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
title_short Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481
title_sort identification and preclinical evaluation of the bicyclic pyrimidine γ-secretase modulator bms-932481
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421538/
https://www.ncbi.nlm.nih.gov/pubmed/30891132
http://dx.doi.org/10.1021/acsmedchemlett.8b00541
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