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Current Medicinal Chemistry

Author(s): Surya K. De*

DOI: 10.2174/0929867331666230821101247

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New Pyrrolopyrimidines as LRRK2 Inhibitors for Treating Parkinson's Disease

Page: [5477 - 5480] Pages: 4

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Abstract

This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).

Keywords: Pyrrolopyrimidines, LRRK2 kinase, Parkinson’s disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), mutation of LRRK2.

[1]
Trinh, J.; Farrer, M. Advances in the genetics of Parkinson disease. Nat. Rev. Neurol., 2013, 9(8), 445-454.
[http://dx.doi.org/10.1038/nrneurol.2013.132] [PMID: 23857047]
[2]
Paisán-Ruiz, C.; Lewis, P.A.; Singleton, A.B. LRRK2: Cause, risk, and mechanism. J. Parkinsons Dis., 2013, 3(2), 85-103.
[http://dx.doi.org/10.3233/JPD-130192] [PMID: 23938341]
[3]
Gilks, W.P.; Abou-Sleiman, P.M.; Gandhi, S.; Jain, S.; Singleton, A.; Lees, A.J.; Shaw, K.; Bhatia, K.P.; Bonifati, V.; Quinn, N.P.; Lynch, J.; Healy, D.G.; Holton, J.L.; Revesz, T.; Wood, N.W. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet, 2005, 365(9457), 415-416.
[http://dx.doi.org/10.1016/S0140-6736(05)17830-1] [PMID: 15680457]
[4]
Ross, O.A.; Soto-Ortolaza, A.I.; Heckman, M.G.; Aasly, J.O.; Abahuni, N.; Annesi, G.; Bacon, J.A.; Bardien, S.; Bozi, M.; Brice, A.; Brighina, L.; Van Broeckhoven, C.; Carr, J.; Chartier-Harlin, M.C.; Dardiotis, E.; Dickson, D.W.; Diehl, N.N.; Elbaz, A.; Ferrarese, C.; Ferraris, A.; Fiske, B.; Gibson, J.M.; Gibson, R.; Hadjigeorgiou, G.M.; Hattori, N.; Ioannidis, J.P.A.; Jasinska-Myga, B.; Jeon, B.S.; Kim, Y.J.; Klein, C.; Kruger, R.; Kyratzi, E.; Lesage, S.; Lin, C.H.; Lynch, T.; Maraganore, D.M.; Mellick, G.D.; Mutez, E.; Nilsson, C.; Opala, G.; Park, S.S.; Puschmann, A.; Quattrone, A.; Sharma, M.; Silburn, P.A.; Sohn, Y.H.; Stefanis, L.; Tadic, V.; Theuns, J.; Tomiyama, H.; Uitti, R.J.; Valente, E.M.; van de Loo, S.; Vassilatis, D.K.; Vilariño-Güell, C.; White, L.R.; Wirdefeldt, K.; Wszolek, Z.K.; Wu, R.M.; Farrer, M.J. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: A case–control study. Lancet Neurol., 2011, 10(10), 898-908.
[http://dx.doi.org/10.1016/S1474-4422(11)70175-2] [PMID: 21885347]
[5]
Jaleel, M.; Nichols, R.J.; Deak, M.; Campbell, D.G.; Gillardon, F.; Knebel, A.; Alessi, D.R. LRRK2 phosphorylates moesin at threonine-558: Characterization of how Parkinson’s disease mutants affect kinase activity. Biochem. J., 2007, 405(2), 307-317.
[http://dx.doi.org/10.1042/BJ20070209] [PMID: 17447891]
[6]
Dzamko, N.; Deak, M.; Hentati, F.; Reith, A.D.; Prescott, A.R.; Alessi, D.R.; Nichols, R.J. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem. J., 2010, 430(3), 405-413.
[http://dx.doi.org/10.1042/BJ20100784] [PMID: 20659021]
[7]
Guo, L.; Gandhi, P.N.; Wang, W.; Petersen, R.B.; Wilson-Delfosse, A.L.; Chen, S.G. The Parkinson’s disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase thatstimulates kinase activity. Exp. Cell Res., 2007, 313(16), 3658-3670.
[http://dx.doi.org/10.1016/j.yexcr.2007.07.007] [PMID: 17706965]
[8]
West, A.B.; Moore, D.J.; Choi, C.; Andrabi, S.A.; Li, X.; Dikeman, D.; Biskup, S.; Zhang, Z.; Lim, K.L.; Dawson, V.L.; Dawson, T.M. Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum. Mol. Genet., 2007, 16(2), 223-232.
[http://dx.doi.org/10.1093/hmg/ddl471] [PMID: 17200152]
[9]
Wile, D.J.; Agarwal, P.A.; Schulzer, M.; Mak, E.; Dinelle, K.; Shahinfard, E.; Vafai, N.; Hasegawa, K.; Zhang, J.; McKenzie, J.; Neilson, N.; Strongosky, A.; Uitti, R.J.; Guttman, M.; Zabetian, C.P.; Ding, Y.S.; Adam, M.; Aasly, J.; Wszolek, Z.K.; Farrer, M.; Sossi, V.; Stoessl, A.J. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies. Lancet Neurol., 2017, 16(5), 351-359.
[http://dx.doi.org/10.1016/S1474-4422(17)30056-X] [PMID: 28336296]
[10]
Sosero, Y.L.; Gan-Or, Z. LRRK2 and Parkinson’s disease: From genetics to targeted therapy. Ann. Clin. Transl. Neurol., 2023, 10(6), 850-864.
[http://dx.doi.org/10.1002/acn3.51776] [PMID: 37021623]