FP-040: CNS Diseases

Aldehyde dehydrogenase 2 (ALDH2) is an enzyme in the mitochondria that oxidizes toxic aldehydes into non-toxic acids for excretion. ALDH2 activator FP-045’s follow-on FP-040 series, are new chemical entities developed through rational drug design. It has been proven in animal experiments to increase ALDH2 activity effectively, accelerate the metabolism of toxic aldehydes in ischemic tissues, reduce oxidative stress, protect mitochondria, and enhance skeletal muscle activity. FP-040 compounds showed good safety and efficacy profiles results in animal models of cardiorenal metabolic disease, PAD and Alzheimer’s disease.

Accumulating data highlights the deleterious effects of increased aldehydic load and reactive oxygen species (ROS) in neuropathology, such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis. Mitochondria ALDH2 has been demonstrated to restore mitochondrial function via detoxifying endogenous and exogenous aldehydes and engaging in cellular signal transduction fundamental for cell adaption and survival. Therefore, as a tissue with particularly high mitochondrial content and oxidative rate in the brain, the function of ALDH2 in protection against deleterious aldehyde and ROS buildups is remarkably critical. Substantial evidence has demonstrated that a small molecule ALDH2 activator, represented as Alda-1, reduces neuronal cell death in models of ischemic stroke, Alzheimer's disease, Parkinson's disease, etc. Foresee's novel compound FP-040, similar to FP-045, can enhance the activity of ALDH2 with potency higher than Alda-1, thereby reducing aldehydic load and oxidative stress accumulated in cells and living organisms. In vivo, the valine ester prodrug of FP-040 shows promising pharmacokinetic profile in several mammalian species when administered orally or intravenously. It also exhibits good bioavailability, as demonstrated by the rapid conversion into an active metabolite of FP-040 via esterase hydrolysis.

Moreover, preliminary animal studies data showed that treatment of FP-040 benefited the diseased animals. Overall, the FP-040 series present features, including their physical, chemical, and biological properties and efficacy, to become promising candidates for drug development. Upon completing several clinical studies of the FP-045 program across several indications, Foresee will advance the development of FP-040 as a potential therapy for treating aldehyde-induced diseases.