Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
Abstract
1. Introduction
2. Results
2.1. Synthesis of Compounds
2.2. Overview of Activities and SAR
2.3. Pharmacokinetic Studies
2.4. Pharmacological Studies
2.4.1. LPS-Induced Inflammation Studies
2.4.2. MPTP Model
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.1.1. Synthesis of (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,5,7-chromantriol ((−)-gallocatechin, GC)
4.1.2. Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (2)
4.1.3. Synthesis of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (3a)
4.1.4. Synthesis of 3,4,5-tris(benzyloxy)-2,6-difluorobenzoic acid (3b)
4.1.5. Synthesis of 3, 4-bis(benzyloxy)-2-fluoro-5-methoxybenzoic acid (3c)
4.1.6. Synthesis of benzyl 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate (3d)
4.1.7. Synthesis of 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoic acid (3e)
4.1.8. Synthesis of 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoic acid (3f)
4.1.9. Synthesis of 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoic acid (3g)
4.1.10. Synthesis of 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoic acid (3h)
4.1.11. General Procedure for Synthesis of Compounds 4a–h
4.1.12. General Procedure for Synthesis of Compounds 1a–h
4.2. Kinase Assays
4.3. Pharmacokinetic Assays
4.4. Pharmacological Studies
4.4.1. LPS-Induced Inflammation Model
4.4.2. MPTP Model
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | R1 | R2 | R3 | DYRK1A IC50 (nM) | DYRK1B IC50 (nM) | DYRK2 IC50 (nM) |
---|---|---|---|---|---|---|
EGCG | H | OH | H | 220 | 257 | 1488 |
AZ-191 | 98 | 27 | 1720 | |||
GCG | H | OH | H | 121 | 132 | 574 |
GCG-3”OMe | H | OMe | H | 206 | ||
1a | H | OH | F | 35 | 42 | 258 |
1b | F | OH | F | 28 | 45 | 181 |
1c | H | OMe | F | 73 | 79 | 331 |
1d | F | OMe | H | 152 | ||
1e | F | OMe | F | 125 | ||
1f | H | OCHF2 | H | 252 | ||
1g | H | OCHF2 | F | 136 | ||
1h | F | OiPr | F | 356 |
1c | 1b | EGCG | ||||||
---|---|---|---|---|---|---|---|---|
Parameter | Unit | i.v. (5mg/kg) | IN (60 mg/kg) | PO (100 mg/kg) | PO (100 mg/kg) | PO (100 mg/kg) | ||
Plasma | Brain | Plasma | Brain | Plasma | Plasma | |||
T1/2 | h | 3.2 | 4.8 | NRV | 4.7 | NRV | 12.7 | 5.02 |
Tmax | h | 0 | 2 | 0.5 | 1 | 2 | 0.5 | |
Tlast | h | 10 | 24 | 8 | 24 | 24 | 24 | |
Cmax | ng/mL | 657 | 2353 | 18 | 684 | 110 | 131 | 55 |
AUC0-t | ng h/mL | 1276 | 15763 | 116 | 4174 | 2392 | 379 | 360 |
AUC (0-inf) | ng h/mL | 1393 | 16079 | NRV | 4275 | NRV | 472 | 395 |
F | % | NA | >100 | 16 | N/A | 2 |
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Araldi, G.L.; Hwang, Y.-W. Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease. Pharmaceuticals 2023, 16, 443. https://doi.org/10.3390/ph16030443
Araldi GL, Hwang Y-W. Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease. Pharmaceuticals. 2023; 16(3):443. https://doi.org/10.3390/ph16030443
Chicago/Turabian StyleAraldi, Gian Luca, and Yu-Wen Hwang. 2023. "Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease" Pharmaceuticals 16, no. 3: 443. https://doi.org/10.3390/ph16030443
APA StyleAraldi, G. L., & Hwang, Y.-W. (2023). Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease. Pharmaceuticals, 16(3), 443. https://doi.org/10.3390/ph16030443