Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 5; pp. 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: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2018
• 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; Ncotinamide; Obesity; Diabetes; Nicotinamide N-methyltransferase (NNMT); Methyl-nicotinamide (MNA)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.01.058

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%.
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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.