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

Bioorg Med Chem Lett. 2015 Apr 1;25(7):1621-6. doi: 10.1016/j.bmcl.2015.01.051. Epub 2015 Feb 10.

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.

Keywords: Alzheimer’s disease; Amyloid-beta; Cytochrome P450 3A4; Drug–drug-interactions; Gamma secretase modulator; Natural product; Semisynthesis; Sterol.

MeSH terms

  • Animals
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Cytochrome P-450 CYP3A / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Rats
  • Rats, Sprague-Dawley
  • Steroids / chemistry
  • Steroids / pharmacology*
  • Structure-Activity Relationship

Substances

  • Azetidines
  • Biological Products
  • SPI-1865
  • Steroids
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human