Cyclic sulfonamides as γ-secretase inhibitors for the treatment of Alzheimer's disease

MEDI 287

Dmitri Pissarnitski, dmitri.pissarnitski@spcorp.com1, Zhiqiang Zhao1, Theodros Asberom1, Thomas Bara1, John W. Clader1, William J. Greenlee1, Henry Guzik1, Lynn Hyde2, Hubert Josien1, Wei Li1, Eric M. Parker3, Murali Rajagopalan1, Lili Zhang4, and Amin Nomeir5. (1) Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, (2) Department of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, (3) Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, (4) Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, (5) Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033
Alzheimer's disease (AD) is a progressive degenerative disease of the brain leading to dementia. One of the hallmarks of AD is abnormal accumulation of amyloid-β protein (Aβ) in the brain of AD patients. γ-Secretase is one of the key enzymes leading to the formation of Aβ by intramembrane proteolysis of the parent APP. Herein we describe the development of a series of cyclic sulfonamides resulting in the discovery of low nanomolar, orally bioavailable inhibitors of γ-secretase. In vivo assessment of selected compounds in a transgenic animal model of AD demonstrated reduction of Aβ levels in both plasma and brain.

 

Gamma and Beta Secretase
1:30 PM-5:00 PM, Tuesday, 12 September 2006 Moscone Center -- Room 102, Oral

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006