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Chemistry-led investigations into the mode of action of NAMPT activators, resulting in the discovery of non-pyridyl class NAMPT activators

Research output: Contribution to journalArticlepeer-review

Siyuan Tang, Miguel Garzon Sanz, Oliver Smith, Andreas Krämer, Daniel Egbase, Paul W. Caton, Stefan Knapp, Sam Butterworth

Original languageEnglish
JournalActa Pharmaceutica Sinica B
DOIs
Accepted/In press2022

Bibliographical note

Funding Information: Siyuan Tang was funded by the China Sponsorship Council (No. 201709110169 ). Stefan Knapp and Andreas Krämer are grateful for support by the SGC, a registered charity (number 1097737 ) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP and Takeda. Stefan Knapp and Andreas Krämer were also supported by the Frankfurt Cancer Institute (FCI) and the DKTK translational cancer network. We would like to thank staff at the Swiss Light Source (SLS) for assisting with data collection and for financial support by the European Union Horizon 2020 research and innovation program under grant agreement number 730872 , project CALIPSOplus. Publisher Copyright: © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences

King's Authors

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.

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