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

@article{Hubbs2015MinimizationOD,
  title={Minimization of drug-drug interaction risk and candidate selection in a natural product-based class of gamma-secretase modulators.},
  author={Jed L. Hubbs and Nathan Oliver Fuller and Wesley F. Austin and Ruichao Shen and Jianguo Ma and Zhen Zhen Gong and Jian Li and Timothy D. Mckee and Robyn M. B. Loureiro and Barbara Tate and Jo Ann Dumin and Jeffrey L. Ives and Brian Scott Groton Bronk},
  journal={Bioorganic & medicinal chemistry letters},
  year={2015},
  volume={25 7},
  pages={
          1621-6
        }
}
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… CONTINUE READING
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