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

Alle, Thibault, Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Yao, Yuemang, Lucero, Bobby, Nzou, Goodwell, Demuro, Stefania, Muench, Megan, Vuong, Khoa D., Oukoloff, Killian, Cornec, Anne-Sophie, Francisco, Karol R., Caffrey, Conor R., Lee, Virginia M.-Y., Smith, Amos B., Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Brunden, Kurt R. and Ballatore, Carlo 2023. 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. Journal of Medicinal Chemistry 66 (1) , pp. 435-459. 10.1021/acs.jmedchem.2c01411

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	12 March 2023
Date of Acceptance:	1 December 2022
Last Modified:	06 Jan 2024 05:11
URI:	https://orca.cardiff.ac.uk/id/eprint/157682

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