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 good 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 the 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, in brain, as a tissue with particularly high mitochondrial content and oxidative rate, the function of ALDH2 in protection against deleterious aldehyde and ROS buildups is remarkably critical. Substantial evidence has demonstrated that a small molecule ALDH2 activators, 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, is capable of enhancing the activity of ALDH2 with potency higher than Alda-1, thereby reducing aldehydic load and oxidative stress accumulated in cell and living organisms. In vivo, valine ester prodrug of FP-040 shows a good pharmacokinetic profile in several mammalian species when administered orally or intravenously. It also exhibits good bioavailability as demonstrated by the rapid conversion into active metabolite of FP-040 via esterase hydrolysis.

Moreover, preliminary animal studies data showed that treatment of FP-040 exerted beneficial effect to the diseased animals. Overall, FP-040 series present features, including their physical, chemical, and biological properties as well as efficacy, to become promising candidates for drug development. With the success in completion of Phase I clinical trial of FP-045, Foresee is capable of developing FP-040 into drug in treatment of aldehyde-induced diseases.