Recent advances in the design, synthesis, and biological evaluation of selective DYRK1A inhibitors: a new avenue for a disease modifying treatment of Alzheimer's?

Abstract

With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer's disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer's disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer's disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors.

Figure 1

Scheme depicting different mechanistic pathways by which DYRK1A contributes to neurodegeneration and loss of cognitive functions.

Figure 2

(a) Structures of β-carbolines 1a–c. In vitro IC₅₀ values against DYRK1A are indicated in parentheses. [ATP] = 50 mM; [ATP] = 100 μM; [ATP] = 1 mM. (b) Structures of MPP+ 1d and MPTP 1e.

Figure 3

Structure of DYRK1A inhibiting natural and synthetic phenols and polyphenols. 2, [ATP] = 100 μM;3, [ATP] = 20 μM;4a–b, [ATP] = 15 μM;5a–b, [ATP] = 500–1000 c.p.m./pmol; (73) [ATP] = K_M for each kinase).

Figure 4

Chemical structures of indolocarbazoles 6–8 and 9a, b. Inhibitory activity against DYRK1A is also indicated as percent of inhibition or IC₅₀.

Figure 5

General structures of the most active hits of the virtual screen conducted by Song and co-workers. Activity against DYRK1A is reported in parentheses (SP, substrate phosphorylation, [ATP] = 5 μM; AP, autophosphorylation, [ATP] = 10 nM).^,

Figure 6

General structure of quinazoline-amines 13a–d (Table 2).

Figure 7

General structure of INDY 14a and analogues 14b, c. Activity against DYRK1A is reported in parentheses, [ATP] = 10 μM.

Figure 8

General structure of compounds 15–17 (Tables 3 and 4).⁻

Figure 9

General structure of 3-(6-hydroxyindol-2-yl)-5-(phenyl)pyridine and pyrazine analogues 18a–g (Table 5).

Figure 10

General structure of Chromenoindoles 19 (Table 6).

Figure 11

Structures of the two most potent DYRK1A inhibitors 20 and 21 discovered by virtual screening ([ATP] = 1 μM).

Figure 12

General structure of bis-indole indigoids 22a–d (Table 7).

Figure 13

Structure of 3,6-diamino-1H-pyrazolo[3,4-b]pyridine 23 ([ATP] = 15 μM).

Figure 14

DYRK1A inhibitors originally developed as inhibitors of other kinases. (24a,b, [ATP] = 0.1 mM; 25, [I] = 2 μM, [ATP] = 50 μM; 26, [I] = 10nM, [ATP] = 50 μM).^,

Figure 15

General structures of the tetrahalo-bicycles evaluated against DYRK1A (27a–c, [ATP] = 50 μM; 28, [I] = 10 μM, [ATP] = 50 μM]).^,

Figure 16

Crystal structure binding modes of DYRK1A inhibitors harmine 1a (PDB ID: 3ANR), INDY 14a (PDB ID: 3ANQ), and D15 29 (PDB ID: 2WO6).