New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.
[en] Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Goffin, Eric ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Fraikin, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Abboud, Dayana ; Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Molecular Pharmacology
De Tullio, Pascal ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Beaufour, Caroline; Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France
Botez, Iuliana; Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France
Hanson, Julien ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Danober, Laurence; Institut de Recherches Servier, 125 Chemin de Ronde, F-78290, Croissy-sur-Seine, France
Francotte, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Pirotte, Bernard ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.
Servier [FR] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding text :
This study was supported in part by a grant from Servier and the National Fund for Scientific Research (F.N.R.S., Belgium) from which J. Hanson is a Senior Research associate and P. de Tullio is a Research Director. The technical assistance of S. Counerotte is gratefully acknowledged.
Kew, J.N.C., Kemp, J.A., Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology 179 (2005), 4–29, 10.1007/s00213-005-2200-z.
Frydenvang, K., Pickering, D.S., Kastrup, J.S., Structural basis for positive allosteric modulation of AMPA and kainate receptors. J. Physiol. 600 (2022), 181–200, 10.1113/JP280873.
Chang, P.K.Y., Verbich, D., McKinney, R.A., AMPA receptors as drug targets in neurological disease – advantages, caveats, and future outlook. Eur. J. Neurosci. 35 (2012), 1908–1916, 10.1111/j.1460-9568.2012.08165.x.
Pirotte, B., Francotte, P., Goffin, E., de Tullio, P., AMPA receptor positive allosteric modulators: a patent review. Expert Opin. Ther. Pat. 13 (2013), 615–628, 10.1517/13543776.2013.770840.
Giralt, A., Gomez-Climent, M.A., Alcala, R., Bretin, S., Bertrand, D., Delgado-Garcia, J.M., Perez-Navarro, E., Alberch, J., Gruart, A., The AMPA receptor positive allosteric modulator S 47445 rescues in vivo CA3-CA1 long-term potentiation and structural synaptic changes in old mice. Neuropharmacology 123 (2017), 395–409, 10.1016/j.neuropharm.2017.06.009.
Brogi, S., Campiani, G., Brindisi, M., Butini, S., Allosteric modulation of ionotropic glutamate receptors: an outlook on new therapeutic approaches to treat central nervous system disorders. ACS Med. Chem. Lett. 10 (2019), 228–236, 10.1021/acsmedchemlett.8b00450.
Monteiro-Fernandes, D., Silva, J.M., Soares-Cunha, C., Dalla, C., Kokras, N., Arnaud, F., Billiras, R., Zhuravleva, V., Waites, C., Bretin, S., Sousa, N., Sotiropoulos, I., Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology. Mol. Psychiatr. 26 (2021), 5899–5911, 10.1038/s41380-020-0794-5.
Palmer, C.L., Cotton, L., Henley, J.M., The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol. Rev. 57 (2005), 253–277, 10.1124/pr.57.2.7.
Mansour, M., Nagarajan, N., Nehring, R.B., Clements, J.D., Rosenmund, C., Heteromeric AMPA receptors assemble with a preferred subunit stoichiometry and spatial arrangement. Neuron 32 (2001), 841–853, 10.1016/s0896-6273(01)00520-7.
Armstrong, N., Gouaux, E., Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28 (2000), 165–181, 10.1016/s0896-6273(00)00094-5.
Sobolevsky, A.I., Rosconi, M.P., Gouaux, E., X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462 (2009), 745–756, 10.1038/nature08624.
Ptak, C.P., Ahmed, A.H., Oswald, R.E., Probing the allosteric modulator binding site of GluR2 with thiazide derivatives. Biochemistry 48 (2009), 8594–8602, 10.1021/bi901127s.
Kaae, B.H., Harpsøe, K., Kastrup, J.S.J., Sanz, A.C., Pickering, D.S., Metzler, B., Clausen, R.P., Gajhede, M., Sauerberg, P., Liljefors, T., Madsen, U., Structural proof of a dimeric positive modulator bridging two identical AMPA receptor-binding sites. Chem. Biol. 14 (2007), 1294–1303, 10.1016/j.chembiol.2007.10.012.
Timm, D.E., Benveniste, M., Weeks, A.M., Nisenbaum, E.S., Partin, K.M., Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation. Mol. Pharmacol. 80 (2011), 267–280, 10.1124/mol.110.070243.
Francotte, P., de Tullio, P., Goffin, E., Dintilhac, G., Graindorge, E., Fraikin, P., Lestage, P., Danober, L., Thomas, J.Y., Caignard, D.H., Pirotte, B., Design, synthesis, and pharmacology of novel 7-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors. J. Med. Chem. 50 (2007), 3153–3157, 10.1021/jm070120i.
Francotte, P., de Tullio, P., Podona, T., Diouf, O., Fraikin, P., Lestage, P., Danober, L., Thomas, J.Y., Caignard, D.H., Pirotte, B., Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators. Bioorg. Med. Chem. 16 (2008), 9948–9956, 10.1016/j.bmc.2008.10.036.
Francotte, P., Goffin, E., Fraikin, P., Lestage, P., Van Heugen, J.C., Gillotin, F., Danober, L., Thomas, J.Y., Chiap, P., Caignard, D.H., Pirotte, B., de Tullio, P., New fluorinated 1,2,4-benzothiadiazine 1,1-dioxides: discovery of an orally active cognitive enhancer acting through potentiation of the 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors. J. Med. Chem. 53 (2010), 1700–1711, 10.1021/jm901495t.
Krintel, C., Frydenvang, K., Olsen, L., Kristensen, M.T., de Barrios, O., Naur, P., Francotte, P., Pirotte, B., Gajhede, M., Kastrup, J.S., Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. Biochem. J. 441 (2012), 173–178, 10.1042/BJ20111221.
Francotte, P., Goffin, E., Fraikin, P., Graindorge, E., Lestage, P., Danober, L., Challal, S., Rogez, N., Nosjean, O., Caignard, D.H., Pirotte, B., de Tullio, P., Development of thiophenic analogues of benzothiadiazine dioxides as new powerful potentiators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. J. Med. Chem. 56 (2013), 7838–7850, 10.1021/jm400676g.
Nørholm, A.B., Francotte, P., Olsen, L., Krintel, C., Frydenvang, K., Goffin, E., Challal, S., Danober, L., Botez-Pop, I., Lestage, P., Pirotte, B., Kastrup, J.S., Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold. J. Med. Chem. 56 (2013), 8736–8745, 10.1021/jm4012092.
Francotte, P., Nørholm, A.B., Deva, T., Olsen, L., Frydenvang, K., Goffin, E., Fraikin, P., de Tullio, P., Challal, S., Thomas, J.Y., Iop, F., Louis, C., Botez-Pop, I., Lestage, P., Danober, L., Kastrup, J.S., Pirotte, B., Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors belonging to 4-cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine dioxides and diversely chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. J. Med. Chem. 57 (2014), 9539–9553, 10.1021/jm501268r.
Nørholm, A.B., Francotte, P., Goffin, E., Botez, I., Danober, L., Lestage, P., Pirotte, B., Kastrup, J.S., Olsen, L., Oostenbrink, C., Thermodynamic characterization of new positive allosteric modulators binding to the glutamate receptor A2 ligand-binding domain: combining experimental and computational methods unravels differences in driving forces. J. Chem. Inf. Model. 54 (2014), 3404–3416, 10.1021/ci500559b.
Larsen, A.P., Francotte, P., Frydenvang, K., Tapken, D., Goffin, E., Fraikin, P., Caignard, D.H., Lestage, P., Danober, L., Pirotte, B., Kastrup, J.S., Synthesis and pharmacology of mono-, di-, and trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides combined with X-ray structure analysis to understand the unexpected structure-activity relationship at AMPA receptors. ACS Chem. Neurosci. 7 (2016), 378–390, 10.1021/acschemneuro.5b00318.
Krintel, C., Francotte, P., Pickering, D.S., Juknaitė, L., Pøhlsgaard, J., Olsen, L., Frydenvang, K., Goffin, E., Pirotte, B., J.S. Kastrup JS. Enthalpy-entropy compensation in the binding of modulators at ionotropic glutamate receptor GluA2. Biophys. J. 110 (2016), 2397–2406, 10.1016/j.bpj.2016.04.032.
Goffin, E., Drapier, T., Larsen, A.P., Geubelle, P., Ptak, C.P., Laulumaa, S., Rovinskaja, K., Gilissen, J., de Tullio, P., Olsen, L., Frydenvang, K., Pirotte, B., Hanson, J., Oswald, R.E., Kastrup, J.S., Francotte, P., 7-Phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors with nanomolar potency. J. Med. Chem. 61 (2018), 251–264, 10.1021/acs.jmedchem.7b01323.
Drapier, T., Geubelle, P., Bouckaert, C., Nielsen, L., Laulumaa, S., Goffin, E., Dilly, S., Francotte, P., Hanson, J., Pochet, L., Kastrup, J.S., Pirotte, B., Enhancing action of positive allosteric modulators through the design of dimeric compounds. J. Med. Chem. 61 (2018), 5279–5291, 10.1021/acs.jmedchem.8b00250.
Etsè, K.S., Dorosz, J., McLain Christensen, K., Thomas, J.Y., Botez Pop, I., Goffin, E., Colson, T., Lestage, P., Danober, L., Pirotte, B., Kastrup, J.S., Francotte, P., Development of thiochroman dioxide analogues of benzothiadiazine dioxides as new positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. ACS Chem. Neurosci. 12 (2021), 2679–2692, 10.1021/acschemneuro.1c00255.
Reichel, M., Karaghiosoff, K., Reagents for selective fluoromethylation: a challenge in organofluorine chemistry. Angew. Chem., Int. Ed. Engl. 59 (2020), 12268–12281, 10.1002/anie.201913175.
Petko, K.I., Tolmachev, A.A., Yagupol'skii, L.M., Difluoromethylation of sulfonamides, Russian. J. Org. Chem. 38 (2002), 1030–1034, 10.1023/A:1020813915169.
Groutas, W.C., Houser-Archield, N., Chong, L.S., Venkataraman, R., Epp, J.B., Huang, H., McClenahan, J.J., Efficient inhibition of human leukocyte elastase and cathepsin G by saccharin derivatives. J. Med. Chem. 36 (1993), 3178–3181, 10.1021/jm00073a019.
Groutas, W.C., Epp, J.B., Venkataraman, R., Kuang, R., Truong, T.M., McClenahan, J.J., Prakash, O., Design, synthesis, and in vitro inhibitory activity toward human leukocyte elastase, cathepsin G, and proteinase 3 of saccharin-derived sulfones and congeners. Bioorg. Med. Chem. 4 (1996), 1393–1400, 10.1016/0968-0896(96)00133-2.
Zhang, W., Zhu, L., Hu, J., Electrophilic monofluoromethylation of O-, S-, and N-nucleophiles with chlorofluoromethane. Tetrahedron 63 (2007), 10569–10575, 10.1016/j.tet.2007.08.043.
Prakash, G.K., Ledneczki, I., Chacko, S., Olah, G.A., Direct electrophilic monofluoromethylation. Org. Lett. 10 (2008), 557–560, 10.1021/ol702500u.
Wang, L., Wei, J., Wu, R., Cheng, G., Li, X., Hu, J., Hu, Y., Sheng, R., The stability and reactivity of tri-, di-, and monofluoromethyl/methoxy/methylthio groups on arenes under acidic and basic conditions. Org. Chem. Front. 4 (2017), 214–223, 10.1039/C6QO00674D.
Burnashev, N., Monyer, H., Seeburg, P.H., Sakmann, B., Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8 (1992), 189–198, 10.1016/0896-6273(92)90120-3.
Cowen, M.S., Beart, P.M., Cyclothiazide and AMPA receptor desensitization: analyses from studies of AMPA-induced release of [3H]-noradrenaline from hippocampal slices. Br. J. Pharmacol. 123 (1998), 473–480, 10.1038/sj.bjp.0701638.
Lockhart, B., Iop, F., Closier, M., Lestage, P., S)-2,3-Dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1), a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices. Eur. J. Pharmacol. 401 (2000), 145–153, 10.1016/s0014-2999(00)00433-7.
Pirotte, B., Podona, T., Diouf, O., de Tullio, P., Lebrun, P., Dupont, L., Somers, F., Delarge, J., Morain, P., Lestage, P., Lepagnol, J., Spedding, M., 4H-1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4H-1,2,4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships. J. Med. Chem. 41 (1998), 2946–2959, 10.1021/jm970694v.
Ward, S.E., Harries, M.H., Aldegheri, L., Bradford, A.M., Ballini, E., Dawson, L., Lacroix, L., Pardoe, J., Starr, K., Weil, A., Waters, K., Atack, J.R., Woolley, M., Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile. J. Psychopharmacol. 34 (2020), 93–102, 10.1177/0269881119872198.
Shaffer, C.L., Hurst, R.S., Scialis, R.J., Osgood, S.M., Bryce, D.K., Hoffmann, W.E., Lazzaro, J.T., Hanks, A.N., Lotarski, S., Weber, M.L., Liu, J., Menniti, F.S., Schmidt, C.J., Hajós, M., Positive allosteric modulation of AMPA receptors from efficacy to toxicity: the interspecies exposure-response continuum of the novel potentiator PF-4778574. J. Pharmacol. Exp. Therapeut. 347 (2013), 212–224, 10.1124/jpet.113.204735.
Kiyatkin, E.A., The hidden side of drug action: brain temperature changes induced by neuroactive drugs. Psychopharmacology (Berl) 225 (2013), 765–780, 10.1007/s00213-012-2957-9.
Bliss, T.V.P., Collingridge, G.L., A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361 (1993), 31–39, 10.1038/361031a0.
Whitlock, J.R., Heynen, A.J., Shuler, M.G., Bear, M.F., Learning induces long-term potentiation in the hippocampus. Science 313 (2006), 1093–1097, 10.1126/science.1128134.
Ennaceur, A., Delacour, J., A new one-trial test for neuro-biological studies of memory in rats. 1: behavioral data, Behav. Brain Res. 31 (1988), 47–59, 10.1016/0166-4328(88)90157-x.
Bretin, S., Louis, C., Seguin, L., Wagner, S., Thomas, J.Y., Challal, S., Rogez, N., Albinet, K., Iop, F., Villain, N., Bertrand, S., Krazem, A., Bérachochéa, D., Billiald, S., Tordjman, C., Cordi, A., Bertrand, D., Lestage, P., Danober, L., Pharmacological characterisation of S 47445, a novel positive allosteric modulator of AMPA receptors. PLoS One, 12, 2017, e0184429, 10.1371/journal.pone.0184429.
Keeney, A.J., Hogg, S., Marsden, C.A., Alterations in core body temperature, locomotor activity, and corticosterone following acute and repeated social defeat of male NMRI mice. Physiol. Behav. 74 (2001), 177–184, 10.1016/s0031-9384(01)00541-8.
Jacobson, L.H., Cryan, J.F., Differential sensitivity to the motor and hypothermic effects of the GABAB receptor agonist baclofen in various mouse strains. Psychopharmacology (Berl) 179 (2005), 688–699, 10.1007/s00213-004-2086-1.
Kristensen, L.V., Sandager-Nielsen, K., Hansen, H.H., Kv7 (KCNQ) channel openers induce hypothermia in the mouse. Neurosci. Lett. 488 (2011), 178–182, 10.1016/j.neulet.2010.11.024.
