U01AG076481

Development of Novel NLRP3 Inflammasome Inhibitors for Intervening in Alzheimer's Disease

Neuroinflammation has been recognized as an essential player in the pathogenesis of Alzheimer's Disease (AD). Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a multimeric protein complex that tightly regulates the innate immune responses, has been suggested to have critical roles in AD development and progression. Dysregulation of the NLRP3 inflammasome is responsible for the overproduction of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses and cell death. Thus, the NLRP3 inflammasome represents an attractive drug target for AD and offers promise to provide effective disease-modifying potential.

Over the past several years, our team has successfully developed novel small molecule NLRP3 inflammasome selective inhibitors (NSIS). We originally reported NSIS with sulfonamide-containing chemical scaffolds and have established a small molecule library containing >200 compounds with various biological characteristics. Proof of concept studies of our 1st generation lead NSI in transgenic AD mouse models demonstrated target engagement and in vivo efficacy to reduce neuroinflammation and improve cognitive functions. Our recent medicinal chemistry campaign led to the identification of new lead NSIS with significantly improved potency and binding affinity. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization.

The central hypothesis of this proposal is that structural optimization of the current two preclinical lead NSIS will be achieved by designing new viable analogs and isolating potent and orally available NSIS with improved pharmacokinetic (PK) properties (Aim 1). Additionally, pharmacological suppression of the NLRP3 inflammasome by our NSIS will mitigate neuroinflammation and improve cognitive functions in preclinical AD animal models (Aim 2), which will be further evaluated by preclinical investigational new drug (IND)-enabling studies (Aim 3) to advance to clinical studies.

For our hypothesis, the goal of this application is to accomplish preclinical IND-enabling studies on at least one candidate NSI and prepare for a meeting with the FDA and subsequent IND filing. Three aims are proposed to achieve our objectives. In Aim 1, new analogs of the lead NSIS will be designed, synthesized, and biologically characterized to build a dynamic drug discovery and development pipeline. In Aim 2, selected NSIS from Aim 1 will be tested for PK/PD properties in various animal models, including AD mouse models. In Aim 3, the top candidate NSI identified from Aim 2 will be subjected to IND-enabling studies, including GMP production, GLP toxicology studies in rodents and dogs, and oral formulation development to prepare for IND filing and clinical trials.

The proposed research is highly significant because we are developing a novel class of NSIS that will offer great promise to provide novel and effective therapeutics for AD, a devastating neurodegenerative disorder without a cure currently.

Virginia Commonwealth University

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]

Richmond, Virginia 232191539 United States

Single Zip Code

Alzheimer's Drug-Development Program (U01 Clinical Trial Optional) (PAR-18-820)

Amendment Since initial award the total obligations have increased 318% from $1,426,573 to $5,966,043.