The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors
Abstract
:1. Introduction
2. The Working Hypothesis, Application of Structure-Based Drug Design
2.1. Computational Prediction Based on the Working Hypothesis for mGluR2
2.2. Computational Prediction Based on the Working Hypothesis for mGLuR4
3. Results and Discussion
4. Materials and Methods
- 4-Methyl-3-phenethyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one, 3a. 1H NMR (500 MHz, CDCl3): δ 7.57 (d, 1H); 7.46 (t, 2H); 7.32 (t, 1H); 7.30 (t, 2H), 7.28 (t, 1H); 7.12 (d, 2H); 3.47 (t, J = 7.5 Hz, 2H); 3.18 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H). 13C NMR: 172.6, 152.9, 152.4, 140.8, 140.0, 138.9, 128.9, 128.9, 128.4, 127.9, 127.1, 125.8, 112.5, 34.3, 29.6, 19.4. C20H17N3O2 MW 331.13; ESI-MS m/z 332.0971 [(M + H)+ 90% rel. I.]. HRMS calc’d for C20H18N3O2 (M + H+): 332.1399, found: 332.1396. −0.9 ppm.
- 3-(1,3-Diphenylpropan-2-yl)-4-methyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one, 4a. 1H NMR (500 MHz, CDCl3): δ 7.51 (d, 2H); 7.43 (t, 2H); 7.36 (t, 1H); 7.21 (m, 8H); 7.01 (d, 2H); 3.796 (pentet, J = 7.5 Hz, 1H); 3.268 (d, J = 8 Hz, 4H); 1.86 (s, 3H). 13C NMR: 174.5, 152.8, 151.9, 140.6, 139.8, 138.0, 128.8, 128.5, 127.8, 127.1, 125.6, 113.4, 45.0, 40.8, 18.9. C27H23N3O2 MW 421.18; ESI-MS m/z 422.1432 [(M + H+), 61% rel. I.]. HRMS calc’d for C27H24N3O2 (M + H+): 422.1869, found: 422.1871. 0.5 ppm.
- 3-(2-(4-Chlorophenyl)-2-hydroxyethyl)-4-methyl-6-(p-tolyl)isoxazolo[3,4-d]pyridazin-7(6H)-one, 3h. TLC (SiO2 4:4:1 hexane-EtOAc-DCM) Rf 0.16. 1H NMR (500 MHz, CDCl3): δ 7.42 (d, J = 8.5 Hz, 2H); 7.259 (m, 4H); 7.08 (d, J = 8.5 Hz, 2H); 5.1 (br. m., 1H); 4.04 (dd, J = 7 Hz); 3.69 (dd, J = 15, 7 Hz, 1H); 3.62 (dd, J = 7, 15 Hz); 2.40 (s, 3H); 2.386 (s, 3H). C21H18ClN3O3 MW 395.1; ESI-MS m/z 378.0079 [(35Cl, M-OH+) 47% rel. I.], 379.9991 [(37Cl, M-OH+) 15% rel. I.].
- 4-Methyl-3-phenethyl-6-(p-tolyl)isoxazolo[3,4-d]pyridazin-7(6H)-one, 3c. 1H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8 Hz, 2H); 7.12 (m, 5H); 6.97 (d, J = 8 Hz, 2H); 3.32 (t, J = 8 Hz, 2H); 3.03 (t, J = 8 Hz, 2H); 2.24 (s, 3H); 2.14 (s, 3H). 13C NMR: 172.4, 152.9, 152.4, 139.7, 138.8, 138.2, 137.9, 129.5, 128.9, 128.3, 127.0, 125.6, 112.5, 34.3, 29.6, 21.1, 19.3. C21H19N3O2 MW 345.39; ESI-MS m/z 346.1176 [(M + H)+ 100% rel. I.]. HRMS: calc’d for C21H20N3O2 (M + H+): 346.1556, found: 346.1558. 0.6 ppm.
- 6-(p-Methoxyphenyl)-4-methyl-3-phenethyl-isoxazolo[3,4-d]pyridazin-7(6H)-one, 3d. 1H NMR (400 MHz, CDCl3): δ 7.385 (d, J = 8 Hz, 2H); 7.16–7.22 (m, 3H); 7.7.65 (d, J + 8 Hz, d); 6.89 (d, J = 8 Hz, 2H); 3.73 (s, 3H); 3.38 (t, J = 8 Hz, 2H); 3.11 (t, J = 8 Hz, 2H); 2.20 (s, 3H). 13C NMR: 172.6, 159.0, 153.0, 152.4, 139.8, 138.9, 133.8, 128.9, 127.1,114.1, 55.6, 34.3, 29.6, 19.4. C21H19N3O3 MW: 361.3. HRMS calc’d for C21H20N3O3 (M + H+): 362.1505, found: 362.1506. 0.3 ppm.
- 6-(p-Methoxyphenyl)-3-(1,3-diphenylpropan-2-yl)-4-methyl-isoxazolo[3,4-d]pyridazin-7(6H)-one, 4d. 1H NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8 Hz, 2H); 7.19–7.25 (m, 6H); 7.19 (d, J = 8 Hz, 4H); 6.94 (d, J = 8 Hz, 2H); 3.83 (s, 3H); 3.81 (pentet, J = 8 Hz, 1H); 3.28 (d, J = 8 Hz, 4H); 1.85 (s, 3H). 13C NMR: 174.5, 159.0, 152.9, 151.9, 139.6, 138.0, 133.7, 128.8, 128.6, 126.9, 114.1, 113.4, 55.6, 45.0, 40.8, 19.0. C28H25N3O3 MW: 451.5. HRMS calc’d for C28H26N3O3 (M + H+): 452.1974, Found: 452.1975. 0.2 ppm.
- 6-(3,5-Dichlorophenyl)-4-methyl-3-phenethylisoxazolo[3,4-d]pyridazin-7(6H)-one, 3f. 1H NMR (400 MHz, CDCl3): δ 7.515 (d, J = 4 Hz, 2H); 7.18–7.27 (m, 5H); 7.04 (d, 1H); 3.41 (t, 3 J = 8 Hz, 2H); 3.12 (t, 3 J = 8 Hz, 2H); 2.2 (s, 3H). 13C NMR: 173.0, 152.7, 152.0, 142.1, 140.9, 138.6, 134.8, 128.9, 128.3, 127.2, 124.2, 112.3, 34.2, 29.6, 19.3. C20H15Cl2N3O2 MW: 400.26; ESI-MS m/z 400 [(M + H+), 100% rel. I.]; 402 [(M + H) + 2, 67.7]; 404 [(M + H) + 4, 12.2]. HRMS Calc’d for C20H16Cl2N3O2 400.0620, Found: 400.0622. 0.5 ppm.
- 6-(3,5-Dichlorophenyl)-4-methyl-3-(1,3-diphenylpropan-2-yl)-isoxazolo[3,4-d]pyridazin-7(6H)-one, 4f. 1H NMR (400 MHz, CDCl3): δ 7.532 (d, J = 1.7 Hz, 2H); 7.32 (t, J = 1.7,1H); 7.25–7.19 (m, 6H); 7.01–6.99 (d, J = 6.4 Hz, 4H); 3.81–3.77 (pentet, J = 8 Hz, 1H); 3.30 (s, 2H); 3.28 (s,2H); 1.85 (s, 3H);1.59 (s, 1H). 13C NMR: 175.0, 140.7, 137.9, 134.8, 128.8, 128.5, 127.2, 124.1; 45.2, 40.8, 18.9. C27H21Cl2N3O2 MW: 490.39; HRMS 489 [(M − H)+ 100% rel. I.]; 491 (M + H). Calc’d for C27H21Cl2N3O2 490.3805, Found: 490.1226.
- 6-(3,5-Bistrifluoromethylphenyl)-4-methyl-3-(1,3-diphenylpropan-2-yl)-isoxazolo[3,4-d]pyridazin-7(6H)-one, 4e. 1H NMR (400 MHz, CDCl3): δ 8.13 (s, 2H);7.82(s, 1H); 7.04 (d, 1H); 7.25–7.18 (m, J = 8 Hz, 6H); 7.02–7.00 (d, J = 8 Hz, 4H); 3.82–3.79 (m,1H); 3.31 (s 2H); 3.29 (s, 2H); 1.88(s, 3H); 1.6 (s, 1H). C29H21F6N3O2 MW: 557.49; HRMS m/z 558 [(M + H)+ 100% rel. I.]; 559 [(M + H) + 2]; Calc’d for C29H21F6N3O2 557.49, Found: 557.1153.
- 6-(3,5-Dichlorophenyl)-3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one, 2i. 1H NMR (400 MHz, CDCl3): δ 7. 68 (2H); 7.57 (5H); 7.38 (1H); 5.59 (s, 3H). 13C NMR: δ 208.2, 194.3, 181.6, 170.9, 164.9, 152.7, 152.0, 142.1, 140.7, 134.8, 134.6, 131.2; 129.3, 127.0, 126.7, 125.6, 124.2, 122.6, 112.5, 31.4, 28.7, 18.9. HRMS Calc’d for C18H1135Cl2N3O2 + H 372.0307, Found: 372.0309. 0.5 ppm.
- 6-(3,5-Dichlorophenyl)-3-methyl-4-phenyl-6H,7H-[1,2]oxazolo [3,4-d]pyridazin-7-one, 2j. 1H NMR (400 MHz, CDCl3): δ 7.57–7.56 (d, 5H);7.37(t, 1H); 2.58 (s, 3H).13C NMR 171.0, 152.6, 143.7, 142.2, 134.9, 133.2, 130.5, 129.0, 128.4, 128.0, 124.3, 111.2, 14.0. C18H11Cl2N3O2 MW: 372.205; HRMS m/z 372.0309 [(M + H)+ 100% rel. I.]; 374.0289 (M + H + 2); Calc’d for C18H11Cl2N3O2 372.20538, Found: 372.0309.
- 6-(4-Methoxyphenyl)-3-methyl-4-phenyl-6H,7H-[1,2]oxazolo [3,4-d]pyridazin-7-one, 2k. 1H NMR (400 MHz, CDCl3): δ 7.58–7.53 (t, J = 8, 7H); 7.00–6.98 (d, J = 8, 2H); 3.85(s, 3H); 2.58 (s, 3H).13 C NMR 170.4, 159.0, 152.8, 152.7, 142.6, 133.8, 130.1, 28.8, 128.4, 127.0, 114.0, 111.4, 55.5, 13.9. C19H15N3O3 MW: 333.35; HRMS m/z: 333.1113 [100% rel. I], 334.1147 (20.5%), 335.1181 (2.0%), 334.1084 (1.1%); Calc’d for C19H15N3O3 333.3407, Found: 333.1113.
- 3-Methyl-6-(4-methylphenyl)-4-phenyl-6H,7H-[1,2]oxazolo [3,4-d]pyridazin-7-one, 2l. 1H NMR (400 MHz, CDCl3): δ 7.60–7.58 (m, J = 4, 2H); 7.55–7.53(t, J = 4, 5H); 2.59 (s, 3H); 2.40 (s, 3H).13C NMR 170.6, 152.8, 133.5, 130.3, 128.9, 128.4, 127.7, 115.8, 115.6, 111.4, 14.0. C19H15N3O2 MW: 317.35; HRMS Calc’d for C19H15N3O2 317.12, Found: 317.1164.
- (E)-Ethyl-4-(1-(2-(3,5-dichlorophenyl)hydrazono)ethyl)-5-phenethylisoxazole-3-carboxylate, 7f. 1H NMR (400 MHz, CDCl3): δ 4.34 (q, J = 8 Hz, 2H); 3.17 (t, 2H); 2.98 (t, 2H); 1.80 (s, 3H); 1.32 (t, J = 8 Hz, 3H). C22H21Cl2N3O3 MW: 446.3; ESI-MS m/z 446 [(M + H)+, 100% rel. I.], 448 (M + 3+, 67.4).
- 6-(3,5-Dichlorophenyl)-4-methyl-3-phenethylisoxazolo[3,4-d]pyridazin-7(6H)-one, 3f. 1H NMR (400 MHz, CDCl3): δ 7.515 (d, J = 4 Hz, 2H); 7.18–7.27 (m, 5H); 7.04 (d, 1H); 3.41 (t, 3 J = 8 Hz, 2H); 3.12 (t, 3 J = 8 Hz, 2H); 2.2 (s, 3H). 13C NMR: 173.0, 152.7, 152.0, 142.1, 140.9, 138.6, 134.8, 128.9, 128.3, 127.2, 124.2, 112.3, 34.2, 29.6, 19.3. C20H15Cl2N3O2 MW: 400.26; ESI-MS m/z 400 [(M + H)+, 100% rel. I.); 402 (M + H+2, 67.7); 404 (M + H + 4, 12.2). HRMS Calc’d for C20H16Cl2N3O2 400.0620, Found: 400.0622. 0.5 ppm.
- 6-(3,5-Dichlorophenyl)-4-methyl-3-(2-(naphthalen-1-yl)ethyl)isoxazolo[3,4-d]pyridazin-7(6H)-one, 3g. 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8 Hz, 1H); 7.90 (d, J = 8 Hz, 1H); 7.79 (d, J = 8 Hz, 1H); 7.37–7.61 (m, H); 7.56 (d, J = 2 Hz, 2H); 7.35 (t, 1H); 7.35 (d, J = 2 Hz, 1H); 7.21 (d, J = 8 Hz, 1H), 3.675 (dd, 2H): 3.64 (dd, 2H); 2.00 (s, 3H). 13C NMR: δ 173.0, 152.7, 152.0, 142.1, 140.7, 134.8, 134.6, 131.2; 129.3, 127.0, 126.7, 125.6. 124.2, 122.6, 112.5, 31.4, 28.7, 18.9. C24H17Cl2N3O2 MW: 450.32; ESI-MS m/z 450 [(M + H)+,100% rel. I.]; 452 (M + H+2, 68.9); 452 (M + H+4, 13.1). HRMS Calc’d for C24H18Cl2N3O2 450.0776, Found: 450.0775. −0.2 ppm.
- 1-p-Tolyl-3-methyl-(4-p-Chlorocinnamyl)-5-amino-pyrazole, 15c. Ar1 = p-ClC6H4; Ar2 = p-CH3C6H4; C20H19ClN3O MW 352.8, ESI-MS: m/z 352.1 (100, M+)); 354.1 (M + 2+, 35).
- 1-p-Anisyl-3- methyl -(4-p-Chlorocinnamyl)-5-amino-pyrazole, 15d. Ar1 = p-ClC6H4; Ar2 = p- CH3OC6H4; C20H19ClN3O2 MW 368.8, m/z 368.1 (100, M+); 370.1 (M + 2+, 35).
- 1-[3,5-Dichlorophenyl]-3-methyl-(4-p-Methoxycinnamyl)-5-amino-pyrazole, 15f Ar1 = p-CH3OC6H4; Ar2 = 3,5-Cl2C6H3; C20H18Cl2N3O2 MW: 403.28; ESI-MS m/z 402 (100% rel. I.), 404 (M + 2, 65.5); 406 (M + 4, 11).
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
List of Abbreviations
Ar | Aryl |
CDCl3 | Deuterated chloroform |
CHARMm | Chemistry at Harvard Macromolecular Mechanics |
CNS | Central nervous system |
DCM | Dichloromethane or methylene chloride |
ESI | Electrospray ionization |
GPCR | G-protein-Coupled Receptor |
mGluR | Metabotropic glutamate receptor |
HPLC | High-performance liquid chromatography |
HRMS | High-resolution mass spectrometry |
IP | Isolated and purified yield |
LDA | Lithium diisopropyl amide |
LiHMDS | Lithium hexamethyl disilazide |
LM&EQ | Lateral metalation and electrophilic quenching |
MHz | Mega Hertz |
MS | Mass spectrometry |
NMR | Nuclear magnetic resonance |
ON | Overnight |
PDB | Protein data bank |
PTSA | p-Toluenesuflonic acid |
RMS | Root mean squared gradient |
RSM | Yield based on recovered starting material |
7TM | Seven-transmembrane receptor |
THF | tetrahydro furan |
[3,4-d] isoxazolo | [3,4-d] pyridazinone |
VFD | Venus flytrap domain or glutamate binding domain of mGluR2 and 4 |
References
- Conn, P.J.; Christopoulos, A.; Lindsley, C.W. Allosteric Modulators of GPCRs: A Novel Approach for the Treatment of CNS Disorders. Nat. Rev. Drug Discov. 2010, 8, 41–54. [Google Scholar] [CrossRef]
- Conn, P.J.; Lindsley, C.W.; Meiler, J.; Niswender, C.M. Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs for Treating CNS Disorders. Nat. Rev. Drug Discov. 2014, 13, 692–708. [Google Scholar] [CrossRef] [PubMed]
- Engers, J.L.; Rodriguez, A.L.; Konkol, L.C.; Morrison, R.D.; Thompson, A.D.; Byers, F.W.; Blobaum, A.L.; Chang, S.; Venable, D.F.; Loch, M.T.; et al. Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents. J. Med. Chem. 2015, 58, 7485–7500. [Google Scholar] [CrossRef]
- Volpi, C.; Fallarino, F.; Mondanelli, G.; Macchiarulo, A.; Grohmann, U. Opportunities and Challenges in Drug Discovery Targeting Metabotropic Glutamate Receptor 4. Expert Opin. Drug Discov. 2018, 13, 411–423. [Google Scholar] [CrossRef] [PubMed]
- Crupi, R.; Impellizzeri, D.; Cuzzocrea, S. Role of Metabotropic Glutamate Receptors in Neurological Disorders. Front. Mol. Neurosci. 2019, 12, 20. [Google Scholar] [CrossRef]
- Bai, M. Dimerization of G-Protein-Coupled Receptors: Roles in Signal Transduction. Cell. Signal. 2004, 16, 175–186. [Google Scholar] [CrossRef] [PubMed]
- De Filippis, B.; Lyon, L.; Taylor, A.; Lane, T.; Burnet, P.W.J.; Harrison, P.J.; Bannerman, D.M. The Role of Group II Metabotropic Glutamate Receptors in Cognition and Anxiety: Comparative Studies in GRM2-/-, GRM3-/- and GRM2/3-/- Knockout Mice. Neuropharmacology 2015, 89, 19–32. [Google Scholar] [CrossRef]
- Niswender, C.M.; Conn, P.J. Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease. Ann. Rev. Pharmacol. Toxicol. 2010, 50, 295–322. [Google Scholar] [CrossRef]
- Renzi, G.; Dal Piaz, V. Ricerche Su Alcuni 3-Carbetossi-Isossazoli-4,5-Disostituiti. Gazz. Chim. It. 1965, 95, 1478–1491. [Google Scholar]
- Renzi, G.; Pinzauti, S. Nuovi Derivati Del Systema Isossazolo-[3,4-d]Piridazin-7-One. Farm. Ed. Sci. 1969, 24, 885–892. [Google Scholar]
- Campana, C.; Mirzaei, J.; Koerner, C.; Gates, C.; Natale, N.R. 3-(1,3-Diphenylpropan-2-yl)-4-methyl-6-phenylisoxazolo[3,4-d] pyridazin-7(6H)-one. Acta Cryst. 2013, E69, o1680. [Google Scholar] [CrossRef] [PubMed]
- Gates, C.; Backos, D.S.; Reigan, P.; Kang, H.J.; Koerner, C.; Mirzaei, J.; Natale, N.R. Isoxazolo[3,4-d]Pyridazinones Positively Modulate the Metabotropic Glutamate Subtypes 2 and 4. Bioorg. Med. Chem. 2018, 26, 4797–4803. [Google Scholar] [CrossRef] [PubMed]
- Wu, H.; Wang, C.; Gregory, K.J.; Han, G.W.; Cho, H.P.; Xia, Y.; Niswender, C.M.; Katritch, V.; Meiler, J.; Cherezov, V.; et al. Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator. Science 2014, 344, 58–64. [Google Scholar] [CrossRef] [PubMed]
- Brooks, B.R.; Brooks, C.L.; Mackerell, A.D.; Nilsson, L.; Petrella, R.J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; et al. CHARMM: The Biomolecular Simulation Program. J. Comput. Chem. 2009, 30, 1545–1614. [Google Scholar] [CrossRef]
- Onufriev, A.; Case, D.A.; Bashford, D. Effective Born Radii in the Generalized Born Approximation: The Importance of Being Perfect. J. Comput. Chem. 2002, 23, 1297–1304. [Google Scholar] [CrossRef]
- Koska, J.; Spassov, V.Z.; Maynard, A.J.; Yan, L.; Austin, N.; Flook, P.K.; Venkatachalam, C.M. Fully Automated Molecular Mechanics Based Induced Fit Protein—Ligand Docking Method. J. Chem. Inf. Model. 2008, 48, 1965–1973. [Google Scholar] [CrossRef]
- Feng, Z.; Ma, S.; Hu, G.; Xie, X. Allosteric Binding Site and Activation Mechanism of Class C G-Protein Coupled Receptors: Metabotropic Glutamate Receptor Family. AAPS J. 2015, 17, 737–753. [Google Scholar] [CrossRef]
- Isberg, V.; de Graaf, C.; Bortolato, A. Generic GPCR residue numbers—Aligning topology maps while minding the gaps. Trends Pharmacol. Sci. 2015, 36, 22–31. [Google Scholar] [CrossRef]
- Clark, R.D.; Waldman, M. Lions and tigers and bears, oh my! Three barriers to progress in computer-aided molecular design. J. Comput. Aided Mol. Des. 2012, 26, 29–34. [Google Scholar] [CrossRef]
- Jain, A.N.; Cleves, A.C. Does Your Model Weigh the Same as a Duck? J. Comput. Aided Mol. Des. 2012, 26, 57–67. [Google Scholar] [CrossRef]
- Micetich, R.G.; Chin, C.G. Studies in Isoxazole Chemistry. 111. The Preparation and Lithiation of 3,5-Disubstituted Isoxazoles. Can. J. Chem. 1970, 48, 1371. [Google Scholar] [CrossRef]
- Natale, N.R.; Niou, C.-S. A Facile Synthesis of Functionally Complex Isoxazole Derivatives. Tetrahedron Lett. 1984, 25, 3943–3946. [Google Scholar] [CrossRef]
- Natale, N.R.; McKenna, J.I.; Niou, C.S.; Borth, M.; Hope, H. Metalation of Isoxazolyloxazolines, a Facile Route to Functionally Complex Isoxazoles: Utility, Scope, and Comparison to Dianion Methodology. J. Org. Chem. 1985, 50, 5660–5666. [Google Scholar] [CrossRef]
- Natale, N.R.; Niou, C.-S. Synthesis, Metalation and Electrophilic Quenching of Alkyl-Isoxazole-4-Tertiary Carboxamides. A Critical Comparison of Three Isoxazole Lateral Metalation Methods. Heterocycles 1986, 24, 401. [Google Scholar] [CrossRef]
- Natale, N.R.; Mirzaei, Y.R. The Lateral Metalation of Isoxazoles. A Review. Org. Prep. Proced. Int. 1993, 25, 515–556. [Google Scholar] [CrossRef]
- Zhou, P.; Natale, N.R. Lateral Lithiation of Ethyl 4-Acetyl-5-Methyl-3-Isoxazolyl Carboxylate with 5,5-Dimethyl-l,3-Dioxanyi as a Directing Group. Tetrahedron Lett. 1998, 39, 8249–8252. [Google Scholar] [CrossRef]
- Burkhart, D.J.; Zhou, P.; Blumenfeld, A.; Twamley, B.; Natale, N.R. An Improved Procedure for the Lateral Lithiation of Ethyl 4-Acetyl-5-Methyl-3-Isoxazolyl Carboxylate. Tetrahedron 2001, 57, 8039–8046. [Google Scholar] [CrossRef]
- Burkhart, D.J.; McKenzie, A.R.; Nelson, J.K.; Myers, K.I.; Zhao, X.; Magnusson, K.R.; Natale, N.R. The Catalytic Asymmetric Synthesis of Glutamate Analogues. Org. Lett. 2004, 6, 1285–1288. [Google Scholar] [CrossRef]
- Montesano, F.; Barlocco, D.; Piaz, V.D.; Leonardi, A.; Poggesi, E.; Fanelli, F.; De Benedetti, P.G. Isoxazolo-[3,4-d]-Pyridazin-7-(6H)-Ones and Their Corresponding 4,5-Disubstituted-3-(2H)-Pyridazinone Analogues as New Substrates for A1-Adrenoceptor Selective Antagonists: Synthesis, Modeling, and Binding Studies. Bioorg. Med. Chem. 1998, 6, 925–935. [Google Scholar] [CrossRef]
- Costantino, L.; Rastelli, G.; Gamberini, M.C.; Giovannoni, M.P.; Piaz, V.D.; Vianello, P.; Barlocco, D. Isoxazolo-[3,4-d]-Pyridazin-7-(6H)-One as a Potential Substrate for New Aldose Reductase Inhibitors. J. Med. Chem. 1999, 42, 1894–1900. [Google Scholar] [CrossRef]
- Dal Piaz, V.; Rascón, A.; Dubra, M.E.; Giovannoni, M.P.; Vergelli, C.; Castellana, M.C. Isoxazolo[3,4-d]Pyridazinones and Analogues as Leishmania Mexicana PDE Inhibitors. Il Farmaco 2002, 57, 89–96. [Google Scholar] [CrossRef] [PubMed]
- Dal Piaz, V.; Castellana, M.C.; Vergelli, C.; Giovannoni, M.P.; Gavaldà, A.; Segarra, V.; Beleta, J.; Ryder, H.; Palacios, J.M. Synthesis and Evaluation of Some Pyrazolo[3,4-d]Pyridazinones and Analogues as PDE 5 Inhibitors Potentially Useful as Peripheral Vasodilator Agents. J. Enzyme Inh. Med. Chem. 2002, 17, 227–233. [Google Scholar] [CrossRef] [PubMed]
- Dal Piaz, V.; Giovannoni, M.P.; Ciciani, G.; Barlocco, D.; Giardina, G.; Petrone, G.; Clarke, G.D. 4,5-Functionalized 6-Phenyl-3(2H)-Pyridazinones: Synthesis and Evaluation of Antinociceptive Activity. Eur. J. Med. Chem. 1996, 31, 65–70. [Google Scholar] [CrossRef]
- Barlocco, D.; Cignarella, G.; Dal Piaz, V.; Giovannoni, M.P.; De Benedetti, P.G.; Fanelli, F.; Montesano, F.; Poggesi, E.; Leonardi, A. Phenylpiperazinylalkylamino Substituted Pyridazinones as Potent A1 Adrenoceptor Antagonists. J. Med. Chem. 2001, 44, 2403–2410. [Google Scholar] [CrossRef] [PubMed]
- Giovannoni, M.P.; Vergelli, C.; Ghelardini, C.; Galeotti, N.; Bartolini, A.; Dal Piaz, V. [(3-Chlorophenyl)Piperazinylpropyl]Pyridazinones and Analogues as Potent Antinociceptive Agents. J. Med. Chem. 2003, 46, 1055–1059. [Google Scholar] [CrossRef]
- Dal Piaz, V.; Vergelli, C.; Giovannoni, M.P.; Scheideler, M.A.; Petrone, G.; Zaratin, P. 4-Amino-3(2H)-Pyridazinones Bearing Arylpiperazinylalkyl Groups and Related Compounds: Synthesis and Antinociceptive Activity. Farmaco 2003, 58, 1063–1071. [Google Scholar] [CrossRef]
- Giovannoni, M.P.; Vergelli, C.; Biancalani, C.; Cesari, N.; Graziano, A.; Biagini, P.; Gracia, J.; Gavaldà, A.; Dal Piaz, V. Novel Pyrazolopyrimidopyridazinones with Potent and Selective Phosphodiesterase 5 (PDE5) Inhibitory Activity as Potential Agents for Treatment of Erectile Dysfunction. J. Med. Chem. 2006, 49, 5363–5371. [Google Scholar] [CrossRef]
- Giovannoni, M.P.; Cesari, N.; Vergelli, C.; Graziano, A.; Biancalani, C.; Biagini, P.; Ghelardini, C.; Vivoli, E.; Dal Piaz, V. 4-Amino-5-Substituted-3(2H)-Pyridazinones as Orally Active Antinociceptive Agents: Synthesis and Studies on the Mechanism of Action. J. Med. Chem. 2007, 50, 3945–3953. [Google Scholar] [CrossRef]
- Biancalani, C.; Giovannoni, M.P.; Pieretti, S.; Cesari, N.; Graziano, A.; Vergelli, C.; Cilibrizzi, A.; Di Gianuario, A.; Colucci, M.; Mangano, G.; et al. Further Studies on Arylpiperazinyl Alkyl Pyridazinones: Discovery of an Exceptionally Potent, Orally Active, Antinociceptive Agent in Thermally Induced Pain. J. Med. Chem. 2009, 52, 7397–7409. [Google Scholar] [CrossRef]
- Chimichi, S.; Ciciani, G.; Piaz, V.D.; De Sio, F.; Sarti-Fantoni, P.; Torroba, T. Solid State Photodimerization Reaction of Some 3-Styrylisoxazolo-[3,4-d]Pyridazin-7(6h)-Ones. Heterocycles 1986, 24, 3467–3471. [Google Scholar] [CrossRef]
- Dal Piaz, V.; Pinzauti, S.; Lacrimini, P.J. Condensation of Some 3-Methylisoxazolo[3,4-d]Pyridazin-7(6H)Ones with Aromatic Aldehydes. J. Heterocycl. Chem. 1976, 13, 409–410. [Google Scholar] [CrossRef]
- Dal Piaz, V.; Ciciani, G.; Costanzo, A.; Auzzi, G.; Chimichi, S. 1,2,3,4-Tetrahydro-1,2-diazepine derivatives from isoxazolo[3,4-d]pyridazin-7(6H)-ones. Heterocycles 1984, 22, 1741–1746. [Google Scholar] [CrossRef]
- Dal Piaz, V.; Ciciani, G.; Chimichi, S. New Functionalized Pyrazoles from Isoxazolopyridazinones. Heterocycles 1985, 23, 365–369. [Google Scholar] [CrossRef]
- Casey, M.L.; Kemp, D.S.; Paul, K.G.; Cox, D.D. The Physical Organic Chemistry of Benzisoxazoles. I. The Mechanism of the Base-Catalyzed Decomposition of Benzisoxazoles. J. Org. Chem. 1973, 38, 2294–2301. [Google Scholar] [CrossRef]
- Kemp, D.S.; Casey, M.L. Physical organic chemistry of benzisoxazoles II. Linearity of the brønsted free energy relationship for the base-catalyzed decomposition of benzisoxazoles. J. Am. Chem. Soc. 1973, 95, 6670–6680. [Google Scholar] [CrossRef]
- Röthlisberger, D.; Khersonsky, O.; Wollacott, A.M.; Jiang, L.; DeChancie, J.; Betker, J.; Gallaher, J.L.; Althoff, E.A.; Zanghellini, A.; Dym, O.; et al. Kemp elimination catalysts by computational enzyme design. Nature 2008, 453, 190–197. [Google Scholar] [CrossRef]
- Khersonsky, O.; Röthlisberger, D.; Dym, O.; Albeck, S.; Jackson, C.J.; Baker, D.; Tawfik, D.S. Evolutionary Optimization of Computationally Designed Enzymes: Kemp Eliminases of the KE07 Series. J. Mol. Biol. 2010, 396, 1025–1042. [Google Scholar] [CrossRef]
- Roberts, J.D.; Simmons, H.E., Jr.; Carlsmith, L.A.; Vaughan, C.W. Rearrangement in the reaction of Chlorobenzene-1-C14 with Potassium Amide. J. Am. Chem. Soc. 1953, 75, 3290–3291. [Google Scholar] [CrossRef]
- Goetz, A.E.; Shah, T.K.; Garg, N.K. Pyridynes and indolynes as building blocks for functionalized heterocycles and natural products. Chem. Comm. 2015, 51, 34–45. [Google Scholar] [CrossRef]
- Vitale, P.; Di Nunno, L.; Scilimati, A. Synthesis of N,N-dialkylaminobenzonitriles and halo-(N,N-dialkyl)benzamidines by reaction of halobenzonitriles with lithium amides. Tetrahedron 2011, 67, 6944–6952. [Google Scholar] [CrossRef]
- Di Nunno, L.; Vitale, P.; Scilimati, A. Effect of the aryl group substituent in the dimerization of 3-arylisoxazoles to syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.02,5]octan-4,8-diones induced by LDA. Tetrahedron 2008, 64, 11198–11204. [Google Scholar] [CrossRef]
- Amalric, M.; Lopez, S.; Goudet, C.; Fisone, G.; Battaglia, G.; Nicoletti, F.; Pin, J.P.; Acher, F.C. Group III and Subtype 4 Metabotropic Glutamate Receptor Agonists: Discovery and Pathophysiological Applications in Parkinson’s Disease. Neuropharmacology 2013, 66, 53–64. [Google Scholar] [CrossRef] [PubMed]
- Leach, K.; Gregory, K.J. Molecular Insights into Allosteric Modulation of Class C G Protein-Coupled Receptors. Pharmacol. Res. 2017, 116, 105–118. [Google Scholar] [CrossRef] [PubMed]
- Panarese, J.D.; Engers, W.; Wu, D.; Bronson, Y.-J.J.; Macor, J.E.; Chun, J.; Rodriguez, A.L.; Felts, A.S.; Engers, A.L.; Loch, J.T.; et al. Discovery of VU2957 (Valiglurax): An MGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease. ACS Med. Chem. Lett. 2018, 10, 255–260. [Google Scholar] [CrossRef]
- Yang, D.; Zhou, Q.; Labroska, V.; Qin, S.; Darbalaei, S.; Wu, Y.; Yuliantie, E.; Xie, L.; Tao, H.; Cheng, J.; et al. G Protein-Coupled Receptors: Structure- and Function-Based Drug Discovery. Signal Transduct. Target. Ther. 2021, 6, 1–27. [Google Scholar] [CrossRef] [PubMed]
- Harpsøe, K.; Boesgaard, M.W.; Munk, C.; Bräuner-Osborne, H.; Gloriam, D.E. Structural Insight to Mutation Effects Uncover a Common Allosteric Site in Class C GPCRs. Bioinformatics 2017, 33, 1116–1120. [Google Scholar] [CrossRef] [PubMed]
- Robichaud, A.J.; Engers, D.W.; Lindsley, C.W.; Hopkins, C.R. Recent Progress on the Identification of Metabotropic Glutamate 4 Receptor Ligands and Their Potential Utility as CNS Therapeutics. ACS Chem. Neurosci. 2011, 2, 433–449. [Google Scholar] [CrossRef]
- Lindsley, C.W.; Emmitte, K.A.; Hopkins, C.R.; Bridges, T.M.; Gregory, K.J.; Niswender, C.M.; Conn, P.J. Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors. Chem. Rev. 2016, 116, 6707–6741. [Google Scholar] [CrossRef]
- Rovira, X.; Malhaire, F.; Scholler, P.; Rodrigo, J.; Gonzalez-Bulnes, P.; Llebaria, A.; Pin, J.-P.P.; Giraldo, J.; Goudet, C. Overlapping Binding Sites Drive Allosteric Agonism and Positive Cooperativity in Type 4 Metabotropic Glutamate Receptors. FASEB J. 2015, 29, 116–130. [Google Scholar] [CrossRef]
- Ferreira, L.G.; Lamba, D.; Consiglio, N.; Delle, R.; Dharmendra, I.; Yadav, K.; Kang, S.; Choi, S.; Basith, S.; Cui, M.; et al. Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design. Front. Pharmacol. 2018, 9, 128. [Google Scholar]
- Gates, C.A. Development of the Novel Isoxazolo[3,4-d]pyridazinone scaffold, Which Positively Modulates the Metabotropic Glutamate Receptor Subtypes 2 and 4. Graduate Student Theses, Dissertations, & Professional Papers 11830. 2022. Available online: https://scholarworks.umt.edu/etd/11830 (accessed on 21 September 2023).
Entry | SM a | Mono-Yield b (%) c | Di-Yield b (%) c | Method | Base | T (°C) |
---|---|---|---|---|---|---|
1 | 2a | 3a (36) | 4a (23) | A | LiHMDS | −78 |
2 | 2a | 3a trace | 4a 38 | A | 2 LiHMDS | −78 |
3 | 2c | 3c 29(45) | A | LiHMDS | −20 | |
4 | 2c | 3h 8 (15) | A | LDA | −25 | |
5 | 2d | 3d 18 (22) | 4d 5 | A | LiHMDS | −40 |
6 | 2d | 3d (33) | 4d 27 (67) | A | LiHMDS | −80 |
7 | 5a | 3f (34) | B | d | ||
8 | 5a | 3g (45) | B | e |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Gates, C.A.; Backos, D.S.; Reigan, P.; Natale, N.R. The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors. Molecules 2023, 28, 6800. https://doi.org/10.3390/molecules28196800
Gates CA, Backos DS, Reigan P, Natale NR. The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors. Molecules. 2023; 28(19):6800. https://doi.org/10.3390/molecules28196800
Chicago/Turabian StyleGates, Christina A., Donald S. Backos, Philip Reigan, and Nicholas R. Natale. 2023. "The Lateral Metalation of Isoxazolo[3,4-d]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors" Molecules 28, no. 19: 6800. https://doi.org/10.3390/molecules28196800