Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase

Compound 12 Human/mouse NNMT enzymatic inhibition (IC50): 0.58/4.5 µM. Inhibition of MNA in U2OS/3T3L1 cell based assay: 0.3/2.1 µM. Human/mouse metabolic stability (% remaining after 30 m): 85/69. In vivo target engagement (MNA reduction, 2 h): ∼80%. [Display omitted] Nicotinamide N-methyltransfera...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-03, Vol.28 (5), p.922-925
Main Authors: Ruf, Sven, Hallur, Mahanandeesha Siddappa, Anchan, Nisha K., Swamy, Indu N., Murugesan, Karthikai Raj, Sarkar, Sayantani, Narasimhulu, Lokesh Kananti, Putta, V.P. Rama Kishore, Shaik, Shama, Chandrasekar, Devaraj Venkatapura, Mane, Vishal Subhash, Kadnur, Sanjay Venkatachalapathi, Suresh, Juluri, Bhamidipati, Ravi Kanth, Singh, Manvi, Burri, Raghunadha Reddy, Kristam, Rajendra, Schreuder, Herman, Czech, Joerg, Rudolph, Christine, Marker, Alexander, Langer, Thomas, Mullangi, Ramesh, Yura, Takeshi, Gosu, Ramachandraiah, Kannt, Aimo, Dhakshinamoorthy, Saravanakumar, Rajagopal, Sridharan
Format: Article
Language:English
Subjects:
Diabetes
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Methyl-nicotinamide (MNA)
Molecular Structure
Ncotinamide
Niacinamide - chemical synthesis
Niacinamide - chemistry
Niacinamide - pharmacology
Nicotinamide N-methyltransferase (NNMT)
Nicotinamide N-Methyltransferase - antagonists & inhibitors
Nicotinamide N-Methyltransferase - metabolism
Obesity
Structure-Activity Relationship
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Summary:Compound 12 Human/mouse NNMT enzymatic inhibition (IC50): 0.58/4.5 µM. Inhibition of MNA in U2OS/3T3L1 cell based assay: 0.3/2.1 µM. Human/mouse metabolic stability (% remaining after 30 m): 85/69. In vivo target engagement (MNA reduction, 2 h): ∼80%. [Display omitted] Nicotinamide N-methyltransferase (NNMT) has been linked to obesity and diabetes. We have identified a novel nicotinamide (NA) analog, compound 12 that inhibited NNMT enzymatic activity and reduced the formation of 1-methyl-nicotinamide (MNA), the primary metabolite of NA by ∼80% at 2 h when dosed in mice orally at 50 mg/kg.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.01.058