Discovery of a Potent Nicotinamide Phosphoribosyltransferase Activator for Improving Aging-associated Dysfunctions

  • J Med Chem. 2024 Feb 17. doi: 10.1021/acs.jmedchem.3c02370.
Sicheng Yang  1 ,  Donghuan Sun  1 ,  Ying Wu  1  2 ,  Shuqiang Chen  1 ,  Yuan Guo  3 ,  Jian Li  4 ,  Guoqiang Dong  1 ,  Chunquan Sheng  1
Affiliations
  • 1. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, China.
  • 2. Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force, Kunming 650032, China.
  • 3. College of Chemistry and Materials Science, Northwest University, Xi'an 710127, China.
  • 4. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
PMID: 38367219 DOI: 10.1021/acs.jmedchem.3c02370
Abstract

Nicotinamide adenine dinucleotide (NAD+) plays a crucial role in the cellular energy metabolism pathway. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme involved in the biosynthesis of NAD+. Herein, a series of new NAMPT activators were designed to increase the NAD+ levels and improve aging-associated dysfunctions. In particular, compound C8 effectively activated NAMPT and promoted the biosynthesis of NAD+. Furthermore, we demonstrated that NAMPT activator C8 possessed excellent antiaging effects both in vitro and in vivo. Activator C8 showed potent activity in delaying aging in senescent HL-7702 cells and extended the lifespan of Caenorhabditis elegans. In a naturally aging mouse model, compound C8 effectively alleviated age-related dysfunctions and markers. Therefore, NAMPT activator C8 represented a promising lead compound for the treatment of age-related diseases.

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