H. Manning
Faculty Member
Last active: 3/22/2018

New structure-activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO.

Li J, Schulte ML, Nickels ML, Manning HC
Bioorg Med Chem Lett. 2016 26 (15): 3472-7

PMID: 27353534 · PMCID: PMC4993599 · DOI:10.1016/j.bmcl.2016.06.041

Translocator protein (TSPO) represents an attractive target for molecular imaging and therapy due to its prevalence and critical roles played in oncology and other pathologies. Based upon our previously optimized pyrazolopyrimidine scaffold, we elucidated new structure activity relationships related to N,N-disubstitutions of the terminal acetamide on pyrazolopyrimidines and further explored the impacts of these substituents on lipophilicity and plasma protein binding. Several novel chemical probes reported here exhibited significantly increased binding affinity, suitable lipophilicity and protein binding compared with contemporary TSPO ligands. We illustrate that N,N-acetamide disubstitution affords opportunities to introduce diverse chemical moieties distal to the central pyrazolopyrimidine core, without sacrificing TSPO affinity. We anticipate that further exploration of N-acetamide substitutions may yield additional TSPO ligands capable of furthering the field of precision medicine.

Copyright © 2016 Elsevier Ltd. All rights reserved.

MeSH Terms (9)

Acetamides Dose-Response Relationship, Drug Humans Ligands Molecular Structure Pyrazoles Pyrimidines Receptors, GABA Structure-Activity Relationship

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