Small molecule therapeutics for neuroinflammation-mediated neurodegenerative disorders

Abstract

Chronically activated microglia and the resulting cascade of neuroinflammatory mechanisms have been postulated to play a critical role in neurodegenerative disorders. Microglia are the main component of the brain's innate immune system and become activated by infection, injury, misfolded proteins or a multitude of other stimuli. Activated microglia release pro-inflammatory and cytotoxic factors that can damage neurons and transform astrocytes to become toxic to neurons as well. Therapeutic approaches aiming to modulate microglia activation may be beneficial to mitigate the progression of inflammatory-mediated neurodegenerative diseases. In this literature review, we provide an overview of recent progress on key microglia targets and discovery of small molecule compounds advancing in clinical trials to minimize neuroinflammation.

Fig. 1. Increasing number of publications from 2000–2020 obtained from a search of the term “neuroinflammation” in SciFinder®.

Fig. 2. Small molecule TLR2 inhibitors.

Fig. 3. TLR4 inhibitors.

Fig. 4. p38/MAPK inhibitors.

Fig. 5. Evolution from initial fragment to development candidate for p38α/MAPK MW150.

Fig. 6. RIPK1 inhibitors.

Fig. 7. Examples of RIPK1 inhibitors from Denali and Genentech.

Fig. 8. Sulfonyl-urea NLRP3 inhibitors.

Fig. 9. N-Cyano sulfoximine NLRP3 inhibitors.

Silke Miller

Maria-Jesus Blanco