-
Tytuł:
-
Microtubule-Stabilizing 1,2,4-Triazolo[1,5- a ]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights.
-
Autorzy:
-
Alle T; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Varricchio C; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF103NB, U.K.
Yao Y; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Philadelphia, Pennsylvania 19104, United States.
Lucero B; Department of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Nzou G; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Philadelphia, Pennsylvania 19104, United States.
Demuro S; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Muench M; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Philadelphia, Pennsylvania 19104, United States.
Vuong KD; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Oukoloff K; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Cornec AS; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, Pennsylvania 19104-6323, United States.
Francisco KR; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Caffrey CR; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Lee VM; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Philadelphia, Pennsylvania 19104, United States.
Smith AB 3rd; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, Pennsylvania 19104-6323, United States.
Brancale A; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF103NB, U.K.
Brunden KR; Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce St., Philadelphia, Pennsylvania 19104, United States.
Ballatore C; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
-
Źródło:
-
Journal of medicinal chemistry [J Med Chem] 2023 Jan 12; Vol. 66 (1), pp. 435-459. Date of Electronic Publication: 2022 Dec 19.
-
Typ publikacji:
-
Journal Article; Research Support, N.I.H., Extramural
-
Język:
-
English
-
Imprint Name(s):
-
Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
-
MeSH Terms:
-
Neurodegenerative Diseases*/drug therapy
Neurodegenerative Diseases*/metabolism
Alzheimer Disease*/drug therapy
Alzheimer Disease*/metabolism
Humans ; Pyrimidines/chemistry ; Microtubules/metabolism ; Tubulin/metabolism ; Structure-Activity Relationship
-
References:
-
J Neurosci. 2010 Oct 13;30(41):13861-6. (PMID: 20943926)
J Med Chem. 2007 Jan 25;50(2):319-27. (PMID: 17228873)
Sci Adv. 2021 May 19;7(21):. (PMID: 34138737)
Brain Res. 2015 Aug 27;1618:299-308. (PMID: 26086366)
Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):227-31. (PMID: 15615853)
Cell Chem Biol. 2017 Jun 22;24(6):737-750.e6. (PMID: 28579361)
Mol Neurodegener. 2018 Nov 7;13(1):59. (PMID: 30404654)
J Med Chem. 2021 Jan 28;64(2):1073-1102. (PMID: 33411523)
J Pharmacol Exp Ther. 2016 May;357(2):432-50. (PMID: 26980057)
Alzheimers Dement. 2020 Oct;16(10):1345-1357. (PMID: 32918367)
Exp Neurol. 2018 Aug;306:243-249. (PMID: 29223322)
Nat Rev Neurosci. 2007 Sep;8(9):663-72. (PMID: 17684513)
Acta Neuropathol Commun. 2016 Sep 29;4(1):106. (PMID: 27687527)
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9):. (PMID: 33619102)
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4980-4982. (PMID: 25819095)
J Med Chem. 2014 Jul 24;57(14):6116-27. (PMID: 24992153)
J Neurosci. 2012 Mar 14;32(11):3601-11. (PMID: 22423084)
-
Substance Nomenclature:
-
0 (Pyrimidines)
0 (Tubulin)
-
Entry Date(s):
-
Date Created: 20221219 Date Completed: 20230113 Latest Revision: 20230207
-
Update Code:
-
20240104
-
PubMed Central ID:
-
PMC9841533
-
DOI:
-
10.1021/acs.jmedchem.2c01411
-
PMID:
-
36534051
-
Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5- a ]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers ( i.e. , the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.
