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={J. Hubbs and Nathan O Fuller and W. Austin and Ruichao Shen and J. Ma and Zhen Gong and J. Li and T. McKee and Robyn M. B. Loureiro and B. Tate and J. Dumin and J. Ives and B. 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… Expand
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