The design, synthesis and α7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives

doi:10.5246/jcps.2018.08.055

Abstract

Abstract:

A series of new 6-substituted 3H-quinazolin-4-ones (3a−3d) were designed, synthesized and evaluated as the type I positive allosteric modulators (PAMs) of human α7 nAChR expressed in Xenopus ooctyes by two-electrode voltage clamp. However, no compound showed a better efficacious PAM than lead compound 2 in the presence of acetylcholine (100 μM). The structure-activity relationship (SAR) analysis suggested that thiazolo[4,5-d]pyrimidin-7(6H)-one was the key biological skeleton.

Key words: 3H-Quinazolin-4-ones, α7 nAChR, Positive allosteric modulators, Structure-activity relationship, Schizophrenia disease

CLC Number:

R916.4

Supporting:

Zongze Huang, Xintong Wang, Ying Meng, Xin Li, Haoran Xiao, Xiling Bian, KeWei Wang, Qi Sun. The design, synthesis and α7 nicotinic acetylcholine receptors positive allosteric modulative evaluation of 3H-quinazolin-4-one derivatives[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(8): 540-552.

References

[1] (a) Jensen, A.A.; Frlund, B.; Liljefors, T.; Krogsgaard-Larsen, P. Neuronal nicotinic acetylcholine receptors: Structural revelations, target identifications, and therapeutic inspirations. J. Med. Chem. 2005, 48, 4705−4745. (b) Gotti, C.; Riganti, L.; Vailati, S.; Clementi, F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr. Pharm. Des. 2006, 12, 407−428. (c) Briggs, C.A.; Grønlien, J.H.; Curzon, P.; Timmermann, D.B.; Ween, H.; Thorin-Hagene, K.; Kerr, P.; Anderson, D. J.; Malysz, J.; Dyhring, T.; Olsen, G.M.; Peters, D.; Bunnelle, W.H.; Gopalakrishnan, M. Role of channel activation in cognitive enhancement mediated by α7 nicotinic acetylcholine receptors. Br. J. Pharmacol. 2009, 158, 1486−1494. (d) Hajós, M.; Rogers, B.N. Targeting α7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr. Pharm. Des. 2010, 16, 538−554.

[2] (a) Seguela, P.; Wadiche, J.; Dineley-Miller, K.; Dani, J.A.; Patrick, J.W. Molecular cloning, functional properties, and distribution of rat brain alpha 7: A nicotinic cation channel highly permeable to calcium. J. Neurosci. 1993, 13, 596−604. (b) Gotti, C.; Clementi, F.; Fornari, A.; Gaimarri, A.; Guiducci, S.; Manfredi, I.; Moretti, M.; Pedrazzi, P.; Pucci, L.; Zoli, M. Structural and functional diversity of native brain neuronal nicotinic receptors. Biochem. Pharmacol. 2009, 78, 703−711.

[3] (a) Xie, X.; Zhang, G.; Zhang, L. Advances on α7 nAChR as targets for drug development. Chin. J. Med. Chem. 2015, 25, 313‒323. (b) Hauser, T.A.; Kucinski, A.; Jordan, K.G.; Gatto, G.J.; Wersinger, S.R.; Hesse, R.A.; Stachowiak, E.K.; Stachowiak, M.K.; Papke, R.L.; Lippiello, P.M.; Bencherif, M. TC-5619: An alpha7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem. Pharmacol. 2013, 355, 32‒37. (c) Wishka, D.G.; Walker, D.P.; Yates, K.M.; Reitz, S.C.; Jia, S.; Myers, J.K.; Olson, K.L.; Jacobsen, E.J.; Wolfe, M.L.; Groppi, V.E.; Hanchar, A.J.; Thornburgh, B.A.; Cortes-Burgos, L.A.; Wong, E.H.F.; Staton, B.A.; Raub, T.J.; Higdon, N.R.; Wall, T.M.; Hurst, R.S.; Walters, R.R.; Hoffmann, W.E.; Hajos, M.; Franklin, S.; Carey, G.; Gold, L.H.; Cook, K.K.; Sands, S.B.; Zhao, S.X.; Soglia, J.R.; Kalgutkar, A.S.; Arneric, S.P.; Rogers, B.N. Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, An agonist of the α7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: Synthesis and structure-activity relationship. J. Med. Chem. 2006, 49, 4425‒4436.

[4] Preskorn, S.H.; Gawryl, M.; Dgetluck, N. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J. Psychiatr. Pract. 2014, 20, 12‒24.

[5] (a) Williams, D.K.; Wang, J.; Papke, R.L. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: Advantages and limitations. Biochem. Pharmacol. 2011, 82, 915−930. (b) Pandya, A.A.; Yakel, J.L. Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies. Biochem. Pharmacol. 2013, 86, 1054−1062.

[6] (a) Faghih, R.; Gopalakrishnan, M.; Briggs, C.A. Allosteric modulators of the α7 nicotinic acetylcholine receptor. J. Med. Chem. 2008, 51, 701−712. (b) Grønlien, J.H.; Hakerud, M.; Ween, H.; Thorin-Hagene, K.; Briggs, C.A.; Gopalakrishnan, M.; Malysz, J. Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol. Pharmacol. 2007, 72, 715−724. (c) Potasiewicz, A.; Hołuj, M.; Kos, T.; Popik, P.; Arias, H.R.; Nikiforuk, A. 3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the a7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats. Neuropharmacol. 2017, 113(Part A), 188–197.

[7] Guerra-Álvarez, M.; Moreno-Ortega, A.J.; Navarro, E.; Fernández-Morales, J.C.; Egea, J,; López, M.G.; Cano-Abad, M.F. Positive allosteric modulation of alpha-7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum. J. Neurochem. 2015, 133, 309−319.

[8] (a) Gotti, C.; Clementi, F.; Zoli, M. Brain nicotinic acetylcholine receptors: Native subtypes and their relevance. Trends Pharmacol. Sci. 2006, 27, 482‒491. (b) Sharma, G.; Vijayaraghavan, S. Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores. Proc. Natl. Acad. Sci. USA. 2001, 98, 4148‒4153. (c) Yakel J.L. Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity. J. Physiol. 2014, 592, 4147‒4153.

[9] (a) Krause, R.M.; Buisson, B.; Bertrand, S.; Corringer, P.J.; Galzi, J.L.; Changeux, J.P.; Bertrand, D. Ivermectin: A positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 1998, 53, 283‒294. (b) Lopes, C.; Pereira, E.F.; Wu, H.Q.; Purushottamachar, P.; Njar, V.; Schwarcz, R.; Albuquerque, E.X. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at α7 nicotinic receptors. J. Pharmacol. Exp. Ther. 2007, 322, 48‒58. (c) Zwart, R.; Filippi, G.D.; Broad, L.M.; McPhie, G.I.; Pearson, K.H.; Baldwinson, T.; Sher, E. 5-Hydroxyindole potentiates human α7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices. Neuropharmacology. 2002, 43, 374‒384. (d) Grønlien, J.H.; Håkerud, M.; Ween, H.; Thorin-Hagene, K.; Briggs, C.A.; Gopalakrishnan, M.; Malysz, J. Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol. Pharmacol. 2007, 72, 715‒724. (e) Ng, H.J.; Whittemore, E.R.; Tran, M.B.; Hogenkamp, D.J.; Broide, R.S.; Johnstone, T.B.; Zheng, L.; Stevens, K.E.; Gee, K.W. Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc. Natl. Acad. Sci. USA. 2007, 104, 8059‒8064. (f) Timmermann, D.B.; Grønlien, J.H.; Kohlhaas, K.L.; Nielsen, E.Ø.; Dam, E.; Jørgensen, T.D.; Ahring, P.K.; Peters, D.; Holst, D.; Chrsitensen, J.K.; Malysz, J.; Briggs, C.A.; Gopalakrishnan, M.; Olsen, G.M. An allosteric modulator of the α7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J. Pharmacol. Exp. Ther. 2007, 323, 294‒307. (g) Dunlop, J.; Lock, T.; Jow, B.; Sitzia, F.; Grauer, S.; Jow, F.; Kramer, A.; Bowlby, M.R.; Randall, A.; Kowal, D.; Gilbert, A.; Comery, T.A.; LaRocque, J.; Soloveva, V.; Brown, J.; Roncarati, R. Old and new pharmacology: Positive allosteric modulation of the α7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']dipyrrole-1(2H)-carboxamide). J. Pharmacol. Exp. Ther. 2009, 328, 766‒776. (h) Broad, L.M.; Zwart, R.; Pearson, K.H.; Lee, M.; Wallace, L.;McPhie, G.I.; Emkey, R.; Hollinshead, S.P.; Dell, C.P.; Baker, S.R.; Sher, E. Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J. Pharmacol. Exp. Ther. 2006, 318, 1108‒1117.

[10] (a) Huang, X.; Jiao, W.; Sun, Q.; Wang, K. Pharmacokinetic characterization of a novel α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator LD486 in rat plasma using a validated LC-MS/MS assay. J. Chin. Pharm. Sci. 2016, 25, 517–525. (b) Wang, K.; Sun, Q.; Jiao, W.; Tang, J. Preparation of thiazolopyrimidinone compound and their medical use. Faming Zhuanli Shenqing. 2017, CN 106279211 A 20170104 (Patent in Chinese).

[11] Li, Y.H.; Sun, L.L.; Yang. T.Y.; Jiao, W.X.; Tang, J.S.; Huang, X.M.; Huang, Z.Z.; Meng, Y.; Luo, L.C.; Wang, X.T.; Bian, X.L.; Zhang, F.; Sun, Q.; Wang, K.W. Design and synthesis of novel positive allosteric modulators of alpha7 nicotinic acetylcholine receptors with the ability to rescue auditory gating deficit in mice. J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.7b01492.

[12] De Lucca, G.V.; Shi, Q.; Liu, Q. Small Molecule reversible inhibitors of Bruton's tyrosine kinase (BTK): Structure-activity relationships leading to the identification of 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide (BMS-935177). J. Med. Chem. 2016, 59, 7915–7935.

[13] Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted CuI-catalyzed C-N bond formation between aryl halides and amines or N-containing heterocycles. J. Org. Chem. 2005, 70, 5164–5173.

[14] Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Efficient Copper(I)-catalyzed C–S cross coupling of thiols with aryl halides in water. Eur. J. Org. Chem. 2008, 4, 640–643.

[15] Kabir, M.S.; Lorenz, M.; Van Linn, M.L. A very active Cu-catalytic system for the synthesis of aryl, heteroaryl, and vinyl sulfides. J. Org. Chem. 2010, 75, 3626–3643.

[16] Cameron, K.O.; Kung, D.W.; Kalgutkar, A.S. Discovery and preclinical characterization of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid (PF-06409577), a direct activator of adenosine monophosphate-activated protein kinase (AMPK), for the potential treatment of diabetic nephropathy. J. Med. Chem. 2016, 59, 8068–8081.

[17] Tang, J.; Xie, B.; Bian, X.; Xue, Y.; Wei, N.; Zhou, J.; Hao, Y.; Li, Gang.; Zhang, L.; Wang, K. Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B. Acta Pharmacol. Sin. 2015, 36, 800–812.