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

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

Affiliation

  • 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.

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