Important Compound Classes
Title
Triazine Derivatives for Treating Diseases Relating to Neurotrophins
Patent Application Number
WO 2019/162702 A1
Publication Date
August 29, 2019
Priority Application
SE 1850217-9 and GB 1810667.4
Priority Date
February 26, 2018, and 28 June 2018
Inventors
Nordvall, G.; Forsell, P.
Assignee Company
Alzecure Pharma AB, Hälsovägen 7, SE-141 57 Huddinge (SE)
Disease Area
Neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s
Biological Target
Tropomyosin receptor kinase (Trk)
Summary
The tropomyosin receptor kinase (Trk) family of enzymes is tyrosine kinases (TrkA, TrkB and TrkC), which are activated by peptidic hormones of the neurotrophin protein family consisting of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophins (NT3 and NT4). Trks regulate synaptic strength and plasticity in the mammalian nervous system and play a pivotal role in cell differentiation, proliferation, pain, and survival. The development of TrkA kinase inhibitors for chronic pain is hampered by lack of sufficient TrkA selectivity over TrkB and TrkC. TrkB is expressed throughout the body, and the BDNF/TrkB axis is involved in excitatory signaling, long-term potentiation. TrkC is widely expressed in both neural and non-neural tissues and has wide physiological functions in the sympathetic nervous system.
Ligand binding to Trks initiates receptor dimerization and autophosphorylation of the kinase domain, which in turn activates the kinase activity of the receptor. Consequently, further receptor phosphorylation at the Tyr490, Tyr751, and Tyr785 of TrkA could lead to adaptor binding sites that could couple the receptor to SHC adaptor protein 1 (SHC-1), phospholipase Cy1 (PLCy1), and phosphoinositide 3-kinase (PI3K). The various couplings of adaptor proteins result in a number of signaling pathways, which play important role in many key processes in the brain, including long-term potentiation, hippocampal neurogenesis, synaptic plasticity, and so forth. However, there are ligand independent events that can regulate neurotrophin signaling, including the balance between the activity of the receptor tyrosine kinase and tyrosine phosphatases leading to regulation of the levels of phosphorylate receptor. In addition, adenosine and its agonists can mediate the phosphorylation of Trk-receptors, which is also independent of ligand binding.
The fibroblast growth factor (FGF 1–23) and insulin growth factors (IGF 1–2) play key roles in proliferation and differentiation processes, which are involved in changes such as angiogenesis, embryonic development, wound healing, and various signaling pathways. These factors (IGF and FGF) have been implicated in the pathogenesis of neurodegenerative disorders of the central nervous systems, including Alzheimer’s disease (AD). The pathological signatures of AD in the brain has been linked to synapse loss, which is an indicator of cognitive decline in the disease. The basal forebrain cholinergic system is dependent on NGF and cholinergic basal forebrain neurons that expresses the receptor for the NGF TrkA. The neuroprotective/neurorestorative effects mediated by NGF have shown that axotomized cholinergic projections can be rescued by TrkA activation in animals.
Given the neuroprotective and neurorestorative effects of the TrkA/NGF and TrkB/BDNF systems, there has been interest in designing small molecule positive modulators of neurotrophin signaling in treating a number of neurodegenerative diseases such as AD, HIV dementia, Huntington’s disease, Parkinson’s disease, Rett syndrome, Lewy body dementia, and amyotrophic lateral sclerosis. The modulators may also be used for neuroprotection before or after spinal cord injury, hypoxia, stroke, and brain injury. Furthermore, NGF and BDNF systems may regulate metabotrophins in the maintenance of cardiometabolic homeostasis.
However, the neuronal homeostasis of NGF and BDNF in combination with their neuroprotective and neurorestorative effect do not make for ideal drug candidates due to their poor pharmacokinetic properties and especially their limited ability to cross the blood–brain barrier. Most small molecule kinase inhibitors are ATP competitive Type I or Type II binders. Type I inhibitors such as the JAK inhibitor tofacitinib binds in the ATP pocket in a highly conserved aspartate-phenylalanine-glycine (DFG-in) conformation, and Type II inhibitors such as imatinib bind in the ATP pocket, which extend into a less conserved allosteric region. While Type I and II inhibitors can display high levels of selectivity, however, the TrkA, TrkB, and TrkC kinases have no residue difference in the ATP binding site, which pose an extreme challenge in achieving TrkA selectivity over TrkB/C. The need to achieve isoform selectivity within closely related kinases has led to the identification of Type III and Type IV allosteric ligands. Type III ligands like trametinib bind to an adjacent site of the ATP binding site with no interactions in the hinge region of the ATP binding domain.
Therefore, there is need to identify peptides, peptide mimetics, small molecule agonist, or selective modulators of NGF or BDNF. In addition, there is also need for compounds that have improved potency and selectivity to TrkA and TrKB receptors.
Triazine derivatives have been found to be positive modulators of Trk receptors and IGF1R and FGFR1, and have properties that are useful for the treatment of diseases characterized by impaired signaling of neurotrophins. Compounds in this Patent Highlight may be suitable as therapeutic agents for use in disorders such as AD and in patients having the VAL66Met mutation in the BDNF gene.
Definitions
R1 = CH3, phenyl;
R2 = halo, cyano, −N(Ra9)Ra10, 4- to 7-membered heterocyclyl;
q = 0, 1, or 2;
Q = −C(R4)R5–, −O–, −S– or −N(R6)–;
p = m = 0 or 1;
L = −C(R7)R8;
R3 = halo, hydroxy, cyano, or C1–4 alkyl;
R4, R5, R6, R7, and R8 are independent and represent H or C1–2 alkyl.
Key Structures
Biological Assay
High throughput cell-based assay; overexpressing Trks were used to identify positive modulators of TrkA, TrkB, and TrkC. Selected compounds (such as Example 5) was tested in vivo for efficacy using passive avoidance (PA). PA is an aversive learning task-based method that uses electrical foot shock after the test compounds are administered.
Biological Data
The Table below represents compounds
that modulate neurotrophin signaling and the potency is expressed
as EC50 (μM) for individual receptors.
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The author declares no competing financial interest.