Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
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LRRK2 Kinase Inhibitors as Possible Therapy for Parkinson’s Disease and Other Neurodegenerative Disorders Ahmed F. Abdel-Magid* Therachem Research Medilab, LLC. 100 Jade Park, Chelsea, Alabama 35043, United States
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kinase 2 (LRRK2) gene were found to be associated with both genetic and idiopathic PD. Genetic linkage analysis studies have demonstrated that multiple missense mutations in LRRK2 gene lead to an autosomal late onset form of PD. LRRK2 is a member of the ROCO protein family. It is widely expressed in the brain, heart, kidney, lung, liver, and in some immune cells. LRRK2 is a large multidomain protein, which contains Ras GTPase-like (Roc) and mitogen-activated protein kinase kinase kinase (MAPKKK) domains. It also contains N-terminal leucine-rich repeats (LRRs) and multiple protein−protein interaction domains. Studies have shown that LRRK2 displays dual GTPase and kinase activities. In vitro biochemical studies have demonstrated that LRRK2 proteins harboring the PD associated proteins generally display increased kinase activity and decreased GTP hydrolysis compared to the wild type protein. This observation implies that inhibitors of LRRK2 kinase may act to block aberrant LRRK2-dependent signaling in PD. This notion is supported by reports stating that inhibitors of LRRK2 are protective in models of PD. Studies have determined that LRRK2 is expressed in high levels at the PD-affected regions of the brain. LRRK2 is also found in Lewy bodies in patients with neurodegenerative diseases such as PD and Lewy body dementia. Furthermore, elevated levels of LRRK2 mRNA are detected in the striatum of MPTP-treated marmosets (marmosets are monkeys that are used as experimental model to study PD). The increased level of LRRK2 mRNA correlates with the level of L-Dopa induced dyskinesia. These findings suggest that potent, selective, and brain penetrant inhibitors of the LRRK2 kinase may ameliorate L-Dopa induced dyskinesias and could potentially provide a therapeutic treatment for PD. LRRK2 mutations have been associated with Alzheimer’slike pathology; for example, the mutation variant LRRK2 R1628P has been associated with increased risk of developing AD. In addition, mutations in LRRK2 were clinically linked to the transition from mild cognitive impairment to Alzheimer’s disease. These data suggest that LRRK2 inhibitors may also be useful in the treatment of Alzheimer’s disease and other related neurodegenerative disorders. Tau is a highly soluble microtubule-associated protein that is expressed mainly in neuronal axons. Tau hyperphosphorylation has been associated with Alzheimer’s disease and other neurodegenerative diseases such as argyrophilic grain disease, Picks disease, cervicofacial degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, and Parkinson’s linked to chromosome 17 (FTDP-17). These
Title. Indazolyl-spiro[2.3]hexane-carbonitrile Derivatives as LRRK2 Inhibitors, Pharmaceutical Compositions and Uses Thereof Patent Application Number. WO 2019/074810 A1 Publication Date. April 18, 2019 Priority Application. US 62/570,812 Priority Date. October 11, 2017 Inventors. (for US only): Acton, J.; Candito, D. A.; Ellis, J. M.; Fuller, P. H.; Gunaydin, H.; Lapointe, B. T.; Liu, W.; Methot, J. L.; Neelamkavil, S. F.; Pio, B.; Simov, V.; Wood, H. B. Assignee Company. Merck Sharp & Dohme Corp.; 126 East Lincoln Avenue, Rahway, New Jersey 07065−0907, United States Disease Area. Parkinson’s disease (PD), other neurodegenerative diseases, and cancer Biological Target. Leucine-Rich Repeat Kinase 2 (LRRK2) Summary. The invention in this patent application relates to indazolyl-spiro[2.3]hexane-carbonitrile derivatives represented generally by Formula I. These compounds are potent inhibitors of LRRK2 kinase and may potentially be useful in the treatment or prevention of diseases in which the LRRK2 kinase is involved such as Parkinson’s disease and possibly other neurodegenerative diseases and disorders. Parkinson’s disease (PD) is a neurodegenerative disorder that is caused by progressive loss of midbrain dopaminergic neurons. It is associated with impaired motor symptoms such as bradykinesia, rigidity, and resting tremor. PD patients may also suffer from a variety of nonmotor symptoms including cognitive dysfunction, autonomic dysfunction, emotional changes, and sleep disruption. The disease is additionally associated with the formation of abnormal protein aggregates termed Lewy bodies inside nerve cells of the patient’s brain. The progression of both motor and nonmotor symptoms of PD severely impacts patient quality of life. While the majority of PD cases are idiopathic, there are many identified genetic mutations that are linked to a small percentage of PD cases such as those identified in alphasynuclein (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, and LRRK2. However, mutations in leucine-rich repeat © XXXX American Chemical Society
Received: May 13, 2019
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DOI: 10.1021/acsmedchemlett.9b00216 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Key Structures. The inventors described the structures and methods of synthesis of 56 examples of formula I including the following represented examples.
diseases are named collectively as tauopathy disorders. Studies have shown that LRRK2 phosphorylates tubulin-associated tau, and this phosphorylation is enhanced by the kinase activating mutation LRRK2 G2019S. Animal studies show that overexpression of LRRK2 in a tau transgenic mouse model causes the aggregation of insoluble tau and its phosphorylation at multiple epitopes. In addition, hyperphosphorylation of tau has been observed in LRRK2 Rl441G overexpressing transgenic mice. Therefore, the inhibition of LRRK2 kinase activity may be useful in the treatment of tauopathy disorders. Additional studies show that LRRK2 inhibitors can attenuate microglial inflammatory responses and that provides a significant evidence to support a role for LRRK2 in immune cell function in the brain. Neuroinflammation is a common trait in a number of neurodegenerative diseases such as PD, AD, MS, HIV-induced dementia, amyotrophic lateral sclerosis (ALS), ischemic stroke, traumatic brain injury, and spinal cord injury. Researchers have observed high levels of LRRK2 mRNA in muscle biopsy samples taken from ALS patients. Accordingly, LRRK2 kinase inhibitors may be useful in the treatment of neuroinflammation in these disorders. Other recent studies show that LRRK2 is expressed in the cells of the immune system, which suggest it acts to regulate the immune system and modulate its inflammatory responses. Therefore, inhibitors of LRRK2 may be beneficial in the treatment of several immune system diseases such as lymphomas, leukemias, multiple sclerosis, rheumatoid arthritis, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans Syndrome, and others. Increased incidences of certain types of cancers such as renal, breast, lung, prostate, and acute myelogenous leukemia (AML) have been linked to the LRRK2 G2019S mutation. LRRK2 amplification and overexpression were detected in papillary renal and thyroid carcinomas. Thus, the inhibition of LRRK2 kinase activity may additionally be useful in the treatment of cancer. Genome-wide association studies also implicate LRRK2 as a major susceptibility gene in the chronic autoimmune diseases such as Crohn’s disease and leprosy. Because of their therapeutic potential, LRRK2 inhibitors were the subject of many literature reports. Some of these inhibitors are currently in early stages of development, for example, DNL201. The therapeutic promise of LRRK2 inhibitors dictates a need for the discovery and development of additional more effective LRRK2 inhibitors. The compounds of formula I disclosed in this patent application exhibit excellent LRRK2 kinase inhibitory activities and may potentially be useful in the treatment or prevention of Parkinson’s disease as well as other neurodegenerative disorders including those described above.
Biological Assay. • LRRK2 Km ATP LanthaScreen Assay Biological Data. The biological data obtained from testing the above examples are listed in the following table:
Recent Review Articles. 1) Shihabuddin, L. S.; Brundin, P.; Greenamyre, J. T.; Stephenson, D.; Sardi, S. P. J. Neurosci. 2018, 38 (44), 9375−9382. 2) West, A. B. Exp. Neurol. 2017, 298 (Part B), 236−245. 3) Galatsis, P. Expert Opin. Ther. Pat. 2017, 27 (6), 667− 676. 4) Taymans, J.-M.; Greggio, E. Curr. Neuropharmacol. 2016, 14 (3), 214−225.
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AUTHOR INFORMATION
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The author declares no competing financial interest.
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DOI: 10.1021/acsmedchemlett.9b00216 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
