Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators.

Jed L Hubbs,Jeffrey Ives,Barbara Tate,Zhen Gong,Brian S Bronk,Robyn M.B Loureiro,Timothy D Mckee,Jo Ann Dumin,Ruichao Shen,Wesley F Austin,Jianguo Ma,Nathan O Fuller,Jian Li

doi:10.1016/j.bmcl.2015.01.051

Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators.

Jed L Hubbs, Jeffrey Ives + Show 11 more

https://doi.org/10.1016/j.bmcl.2015.01.051

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Journal: Bioorganic & medicinal chemistry letters	Publication Date: Feb 10, 2015
Citations: 9

#Gamma Secretase Modulator #Early Lead Compounds + Show 8 more

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Abstract

Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate.

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