Brain penetrating compounds as promising therapeutics for treatment of neurodegenerative disorders.
An estimated 6.2 million Americans live with Alzheimer’s Disease (AD), and this number is projected to reach over 13 million by 2050 with societal costs expected to rise to $1.1 trillion. A key feature of AD-affected brain tissue is the presence of insoluble tangles within neurons, leading to their dysfunction and subsequent death. These tangles are comprised of tau protein, which is normally responsible for stabilizing microtubules that are critical to normal neuronal function. However, in AD and related neurodegenerative diseases tau dissociates from microtubules, which compromises microtubule function and facilitates tangle formation.
Compounds that cross the blood-brain barrier and stabilize microtubules can normalize microtubule function in AD and related diseases. Such compounds from the triazolopyrimidine chemical family have been demonstrated to be effective in vitro and in mouse models of AD.
A prototype triazolopyrimidine has been shown to be efficacious in normalizing microtubule function, reducing neuronal cell death and attenuating tau tangle formation in a mouse model of AD. Moreover, this prototype compound was also found to reduce the generation of amyloid plaques, another hallmark pathology of AD. Numerous novel compounds from the triazolopyrimidine family bearing various carbon 6 (C6) and carbon 7 (C7) modifications have been designed, synthetized and tested in multiple cellular assays to assess microtubule stabilization. The most promising of these compounds show improved potency and pharmaceutical properties relative to the initial prototype, including excellent brain exposure, greater solubility and enhanced metabolic stability.
- Novel compounds with likely IP protection
- More potent in vitro than previously identified compounds
- Ability to cross the blood-brain barrier
- Based on refined SAR and computation modeling, numerous additional novel compounds are being synthesized with likely enhanced activity
Left panel: Appearance of normal axons within the optic nerve (ON) of control wild-type mice treated with vehicle (WT Vehicle). Middle panel: Appearance of axonal dystrophy in PS19 mice harboring tau tangles used as a model for AD. Right panel: bi-weekly injections of compound 51657 at 10 mg/kg in PS19 mice prevents axonal dystrophy. Scale bar is 2 um.
Therapeutics Stage of Development:
- In vitro activity and in vivo efficacy with safety in AD mouse models
- Preclinical Discovery
PCT conversion of US Provisional Patent applications