Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Structural Biology
2.3. Binding Mode of the High Throughput Screening Hits
2.4. Optimization of a Bisubstrate-Like Inhibitor Series Based on Compound 1
2.5. Combination of Our Bisubstrate-Like Inhibitor Series with the HTS Leads 2 and 3
2.6. Optimization of a Series of Tricyclic Compounds Binding to the Nam Pocket Only
3. Materials and Methods
Crystallographic Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compound Number | R1 | R2 | R3 | R4 | R5 | hNNMT IC50 [µM] | mNNMT IC50 [µM] | HLM/RLM/MLM % Remaining at 1 h |
---|---|---|---|---|---|---|---|---|
1 | OH | Me | H | H | 0.26 | 0.84 | NA | |
6 | H | H | H | H | 1.67 | 2.2 | NA | |
7 | OH | Me | F | H | 0.30 | 0.44 | 30/<5/<5 | |
8 | OH | Me | F | H | >10 | NA | <5/<5/<5 | |
9 | OH | H | F | H | 0.88 | 2.43 | NA | |
10 | OH | Me | F | F | 0.29 | >3 | 7/NA/<5 | |
11 | OH | Me | F | H | 0.2 | 1.87 | <5/NA/<5 | |
12 | OH | Me | H | OMe | 0.008 | 0.0008 | NA | |
13 | OH | Me | F | H | >3 | NA | 73/22/22 |
Compound Number | R1 | R2 | R3 | R4 | R5 | hNNMT IC50 [µM] | mNNMT IC50 [µM] | HLM/RLM/MLM % Remaining at 1 h |
---|---|---|---|---|---|---|---|---|
14 | OH | Me | F | H | 0.49 | 3.48 | <5/NA/<5 | |
15 | OH | Me | F | H | 0.79 | 5.1 | <5/<5/<5 | |
16 | OH | Me | F | H | 1.1 | 1.63 | <5/<5/<5 | |
17 | OH | Me | F | H | >3 | NA | 27/<5/8 | |
18 | OH | Me | F | H | >30 | NA | 35/<5/30 | |
19 | OH | Me | F | H | >10 | NA | NA | |
20 | OH | Me | F | H | >3 | NA | 18/NA/<5 | |
21 | OH | Me | F | H | 0.25 | 1.64 | 20/<5/<5 | |
22 | OH | Me | F | H | >30 | NA | 16/31/<5 | |
23 | OH | Me | F | H | 0.15 | 1.0 | <5/NA/<5 | |
24 | OH | Me | F | H | >10 | NA | <5/NA/<5 |
Compound Number | Structure | hNNMT IC50 [uM] | mNNMT IC50 [uM] | HLM/MLM |
---|---|---|---|---|
25 | 0.75 | >3 | 17/<5 | |
26 | >10 | NA | 12/<5 | |
27 | >30 | NA | NA | |
28 | >3 | >30 | NA | |
29 | >30 | NA | <5/<5 | |
30 | >10 | NA | <5/<5 | |
31 | 0.11 | 0.56 | 23/<5 | |
32 | >30 | NA | 72/32 |
Compound | hNNMT IC50 [µM] | mNNMT IC50 [µM] |
---|---|---|
(2) | 1.3 | 2.3 |
(33) | 2.5 | 3.0 |
Compound | hNNMT IC50 [µM] | mNNMT IC50 [µM] |
---|---|---|
(3) | 0.2 | 0.5 |
(4) | 0.07 | 0.1 |
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Kannt, A.; Rajagopal, S.; Hallur, M.S.; Swamy, I.; Kristam, R.; Dhakshinamoorthy, S.; Czech, J.; Zech, G.; Schreuder, H.; Ruf, S. Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders. Molecules 2021, 26, 991. https://doi.org/10.3390/molecules26040991
Kannt A, Rajagopal S, Hallur MS, Swamy I, Kristam R, Dhakshinamoorthy S, Czech J, Zech G, Schreuder H, Ruf S. Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders. Molecules. 2021; 26(4):991. https://doi.org/10.3390/molecules26040991
Chicago/Turabian StyleKannt, Aimo, Sridharan Rajagopal, Mahanandeesha S. Hallur, Indu Swamy, Rajendra Kristam, Saravanakumar Dhakshinamoorthy, Joerg Czech, Gernot Zech, Herman Schreuder, and Sven Ruf. 2021. "Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders" Molecules 26, no. 4: 991. https://doi.org/10.3390/molecules26040991