U01AG088051

Development of a MT-stabilizing agent for the treatment of tauopathies - Project summary

A group of neurodegenerative diseases referred to as tauopathies, which includes Alzheimer’s disease (AD), are characterized by the presence within brain neurons of inclusions comprised of hyperphosphorylated forms of tau protein.

Tau is normally a microtubule (MT)-associated protein that appears to provide stability to MTs in axons, and excessive phosphorylation of tau in tauopathies promotes its disengagement from MTs and misfolding into oligomeric and fibrillar structures.

This results in increased MT dynamicity, reduced MT density and altered axonal transport in transgenic (TG) mouse tauopathy models, with evidence of similar MT deficits in AD brain that likely contribute to neurodegeneration.

We previously demonstrated that administration of the brain-penetrant MT-stabilizing natural product, epothilone D (EPOD), to TG tauopathy mice resulted in dramatic improvements in several key endpoints, including increased MT density, reduced axonal dystrophy, diminished tau pathology and a lowering of neuron loss with improved cognitive performance.

Although EPOD progressed to a small Phase 1B clinical trial in AD patients, its future clinical advancement is uncertain.

Thus, there would be considerable value in identifying alternative MT-stabilizing agents that could undergo more thorough testing in AD and tauopathy patients.

Towards this end, we evaluated additional MT-stabilizing compounds from different classes, with the goal of identifying alternative and potentially improved candidates for development as disease-modifying drugs for AD and other tauopathies.

This effort led to the identification of a preferred subset of brain-penetrant MT-stabilizing triazolopyrimidines (TPDs) that compared to EPOD and other MT-stabilizing natural products, offer notable advantages, including oral bioavailability and easier synthesis.

With NIH/NIA support (U01/AG061173), a systematic exploration of the structure-activity relationships of TPDs ultimately led to the identification of a structurally novel compound (CNDR-51997) that exhibits improved MT-stabilizing activity and pharmacokinetic profile.

Based on extensive characterization of this compound, including efficacy testing in two different AD mouse models, we believe that CNDR-51997 qualifies as a candidate compound for further development.

Accordingly, the primary objectives of this three-year, late-stage U01 proposal are to develop CNDR-51997 through IND-enabling studies and submit an IND application.

San Diego University Of California

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

La Jolla, California 92093 United States

Single Zip Code

Alzheimer's Drug-Development Program (U01 Clinical Trial Optional) (PAR-22-047)

Amendment Since initial award the total obligations have increased 97% from $2,309,108 to $4,559,463.