Inhibitors of nicotinamide N-methyltransferase designed to mimic the methylation reaction transition state

Organic & Biomolecular Chemistry
Matthijs J van HarenNathaniel I Martin

Abstract

Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyses the methylation of nicotinamide to form N'-methylnicotinamide. Both NNMT and its methylated product have recently been linked to a variety of diseases, suggesting a role for the enzyme as a therapeutic target beyond its previously ascribed metabolic function in detoxification. We here describe the systematic development of NNMT inhibitors derived from the structures of the substrates involved in the methylation reaction. By covalently linking fragments of the NNMT substrates a diverse library of bisubstrate-like compounds was prepared. The ability of these compounds to inhibit NNMT was evaluated providing valuable insights into the structural tolerances of the enzyme active site. These studies led to the identification of new NNMT inhibitors that mimic the transition state of the methylation reaction and inhibit the enzyme with activity on par with established methyltransferase inhibitors.

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Citations

Feb 28, 2018·Scientific Reports·Aimo KanntSaravanakumar Dhakshinamoorthy
Jan 3, 2021·Molecular Neurobiology·Altin KocinajRichard B Parsons
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Aimo KanntSven Ruf
Jul 7, 2020·Organic Letters·Ludovic DecultotMatthew D Shair
May 25, 2021·Drug Discovery Today·Yongzhi GaoMatthijs J van Haren
May 22, 2021·Pigment Cell & Melanoma Research·Roberto CampagnaMonica Emanuelli
Jul 17, 2021·ACS Medicinal Chemistry Letters·Kyohei HayashiHidenori Mikamiyama
Mar 19, 2019·Journal of Medicinal Chemistry·Dongxing ChenRong Huang
Jan 11, 2018·Journal of Medicinal Chemistry·Nicolas BabaultJian Jin
Aug 10, 2021·BioMed Research International·Jie-Ru LiuJiang-Hua Li
Oct 8, 2019·Journal of Medicinal Chemistry·Rocco L PolicarpoMatthew D Shair
Jul 3, 2019·Journal of Medicinal Chemistry·Yongzhi GaoNathaniel I Martin
Aug 31, 2021·RSC Medicinal Chemistry·Iredia D Iyamu, Rong Huang

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