Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators.
10.1016/j.apsb.2022.07.016
- Author:
Siyuan TANG
1
;
Miguel GARZON SANZ
1
;
Oliver SMITH
1
;
Andreas KRÄMER
2
;
Daniel EGBASE
3
;
Paul W CATON
3
;
Stefan KNAPP
2
;
Sam BUTTERWORTH
1
Author Information
1. Division of Pharmacy and Optometry, School of Health Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK.
2. Structural Genomics Consortium (SGC), 60438 Frankfurt Am Main, Germany.
3. Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London SE1 1UL, UK.
- Publication Type:Journal Article
- Keywords:
Bioisosteres;
Drug discovery;
Healthy aging;
Medicinal chemistry;
Nicotinamide phosphoribosyl transferase activator
- From:
Acta Pharmaceutica Sinica B
2023;13(2):709-721
- CountryChina
- Language:English
-
Abstract:
The cofactor nicotinamide adenine dinucleotide (NAD+) plays a key role in a wide range of physiological processes and maintaining or enhancing NAD+ levels is an established approach to enhancing healthy aging. Recently, several classes of nicotinamide phosphoribosyl transferase (NAMPT) activators have been shown to increase NAD+ levels in vitro and in vivo and to demonstrate beneficial effects in animal models. The best validated of these compounds are structurally related to known urea-type NAMPT inhibitors, however the basis for the switch from inhibitory activity to activation is not well understood. Here we report an evaluation of the structure activity relationships of NAMPT activators by designing, synthesising and testing compounds from other NAMPT ligand chemotypes and mimetics of putative phosphoribosylated adducts of known activators. The results of these studies led us to hypothesise that these activators act via a through-water interaction in the NAMPT active site, resulting in the design of the first known urea-class NAMPT activator that does not utilise a pyridine-like warhead, which shows similar or greater activity as a NAMPT activator in biochemical and cellular assays relative to known analogues.
