Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease

  • ACS Med Chem Lett. 2012 Apr 9;3(11):892-6. doi: 10.1021/ml300044f.
Wen-Lian Wu  1 ,  Martin Domalski  1 ,  Duane A Burnett  1 ,  Hubert Josien  1 ,  Thomas Bara  1 ,  Murali Rajagopalan  1 ,  Ruo Xu  1 ,  John Clader  1 ,  William J Greenlee  1 ,  Andrew Brunskill  1 ,  Lynn A Hyde  1 ,  Robert A Del Vecchio  1 ,  Mary E Cohen-Williams  1 ,  Lixin Song  1 ,  Julie Lee  1 ,  Giuseppe Terracina  1 ,  Qi Zhang  1 ,  Amin Nomeir  1 ,  Eric M Parker  1 ,  Lili Zhang  1
Affiliations
  • 1. Department of Medicinal Chemistry, Department of Neuroscience, Department of Pharmaceutical Sciences, and Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
PMID: 24900404 DOI: 10.1021/ml300044f
Abstract

An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.

Keywords
Alzheimer’s disease; amyloid; clinical candidate; notch; γ-Secretase inhibitor.