Non-Naturally Occurring Small Molecule Microtubule-Stabilizing Agents: A Potential Tactic for CNS-Directed Therapies

Several independent studies indicate that microtubule (MT)-stabilizing agents hold considerable promise as candidate therapeutics for a wide spectrum of conditions of the central nervous system (CNS), from brain tumors to spinal cord injury, as well as a number of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease, and amyotrophic lateral sclerosis. Although the identification and development of candidate compounds for CNS-directed MT-stabilizing therapies has been a challenge in drug discovery for many years, a growing number of molecules have now been identified that exhibit both MT-stabilizing activity and brain penetration. In this Viewpoint, we will highlight the potential utility of MT-active triazolopyrimidines, phenylpyrimidines, and related classes of non-naturally occurring small molecules that exhibit favorable druglike properties, including brain penetration and oral bioavailability. The mode of action of these small molecules has not as yet been fully elucidated at the molecular level. However, based on all available data, compounds from these classes appear to act on MTs in a potentially unique manner. Further characterization of these molecules may have important ramifications for drug discovery, especially in the area of CNS diseases.