The broad goals of our project are to pharmacologically optimize, mechanistically characterize (in the most appropriate molecular, cellular and transgenic animal models) and complete the entire preclinical development (through IND filing) of a potent orally bioavailable therapeutic compound carefully selected from a novel series of recently discovered gamma-secretase modulators (GSMs) for the treatment of Alzheimer's disease (AD). AD is neurodegenerative disorder that affects regions of the brain associated with learning and memory. AD affects over 24 million people world-wide and is an enormous burden to society. The extent at which it will affect our aging population will continue to escalate. A recently discovered a series of aryl 2-aminothiazole gamma-secretase modulators (AGSMs) that are pharmaceutical-like small organic molecules that are able to lower Abeta42 production without measurably affecting -Secretase-mediated enzymatic processing of other known gamma-secretase substrates such as the Notch-1 receptor. This project will focus on the pharmacological optimization of a series of AGSMs with improved physicochemical properties known as SGSMs. If successful in a number of predictive preclinical studies, these molecules will undergo further IND-enabling preclinical development and ultimately be tested in humans.

Public Health Relevance

Alzheimer's disease is a major neurodegenerative disease that affects over 24 million people world-wide and currently there is no known cure. This disease if left without an appropriate intervening therapeutic will devastate our Healthcare systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS074501-05
Application #
8911866
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Cywin, Charles L
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Raven, Frank; Ward, Joseph F; Zoltowska, Katarzyna M et al. (2017) Soluble Gamma-secretase Modulators Attenuate Alzheimer's ?-amyloid Pathology and Induce Conformational Changes in Presenilin 1. EBioMedicine 24:93-101
Rynearson, Kevin D; Buckle, Ronald N; Barnes, Keith D et al. (2016) Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme. Bioorg Med Chem Lett 26:3928-37
Wagner, Steven L; Zhang, Can; Cheng, Soan et al. (2014) Soluble ?-secretase modulators selectively inhibit the production of the 42-amino acid amyloid ? peptide variant and augment the production of multiple carboxy-truncated amyloid ? species. Biochemistry 53:702-13
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Zhang, Xulun; Hoey, Robert; Koide, Akiko et al. (2014) A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of ?-secretase. J Biol Chem 289:34851-61
Wagner, Steven L; Tanzi, Rudolph E; Mobley, William C et al. (2012) Potential use of ?-secretase modulators in the treatment of Alzheimer disease. Arch Neurol 69:1255-8