Development status

PAI-1 inhibitor: RS5614

PAI-1 is a protein necessary for the dissolution of blood clots (fibrinolysis), but in recent years, a series of findings have revealed that it is involved in cell “regeneration” and “aging”, and is considered to be a therapeutic target for diseases associated with aging and lifestyle. Until now, there has been no clinical application of drugs that can inhibit the activity of the human PAI-1 molecule. We have been working to develop PAI-1 inhibitors with potential applications in regeneration and aging-related diseases.

Based on the crystal structure of the human PAI-1 molecule, we have obtained candidate compounds for PAI-1 inhibition from a virtual compound library using computer engineering. Over the past 10 years, we have synthesized and screened more than 1,400 new inhibitors and evaluated their activity and safety, resulting in the acquisition of RS5614, a candidate compound for clinical development with excellent safety that can be administered orally.

The expression of PAI-1 is high in aged cells, tissues and individuals (klotho mice and humans with Werner syndrome, a well-known disease of premature aging). In the klotho mouse, a model of aging, we found that inhibition of PAI-1 ameliorated all the major symptoms of aging. PAI-1 expression is extremely high in age-related diseases such as cancer, atherosclerosis, chronic obstructive pulmonary disease, diabetes, kidney disease, and Alzheimer’s disease, and administration of a PAI-1 inhibitor can markedly improve the condition of these animal models of disease.

A study of Amish people living in the Midwest, the US, revealed that those without the PAI-1 gene lived about 10 years longer than those with it. Those who lacked the PAI-1 gene were less likely to suffer from diseases such as diabetes.

Pipeline under development