Current studies 2

PAI-1 inhibitor

Plasminogen activator inhibitor 1 (PAI-1) plays a significant role in coagulation and fibroblast fibrosis. PAI-1 is intimately related to the causes of a heart disease, the second cause of death in our country, and that of a cerebrovascular disease, the third cause of death. It is also the biggest cause of becoming a bedridden and a condition of need for long-term care. Curiously, PAI-1 is strongly linked to not only cancer which is the biggest killer in Japan but metabolic syndrome such as obesity and diabetes. PAI-1 deficiency inhibits the appearance of cancer, diabetes and obesity, because it doesn’t trigger thrombosis such as myocardial and brain infarction, venous and pulmonary thrombosis. Thus, PAI-1 plays a key role for a lot of socially important diseases. Therefore the development of PAI-1 will be a significant contribution to medical care and will make a big positive impact on people’s lives, economy and society in Japan.

PAI-1 is a molecular which belongs to Serine Protease Inhibitor Superfamily (SERPIN). SERPIN is a protein group with common structure and widely exists in animals, plants, bacteria and viruses. It has been known that 36 types of SERPIN exist in a human body. However, there have not been successful cases in developing inhibitors of SERPIN, since physiological function remains unsolved in many types of human tissue-specific SERPIN.

Dr. Miyata has found that megsin, a variety of SERPIN, exists specifically in the kidneys and it relates to kidney diseases (Miyata T et al. J Clin Invest. 1998 Aug 15;102:828-36.). As a part of the development of megsin inhibitors, Dr. Miyata tried to create a low-small molecule inhibitor using PAI-1 as a model. Based on the information on X-ray crystal structure analysis, Dr. Miyata have acquired the lead compound of TM5007, using the state-of-the-art SBDD technology. It is particularly worth mentioning that Dr. Miyata has demonstrated that TM5007 with oral has lung fibrosis and antithrombotic effects in animal models, and that for the first time in the world he has succeeded in obtaining a compound of PAI-1 inhibitor (Izuhara Y et al., Arterioscler Thomb Vasc Biol. 2008 Apr;28:672-7). Yet, there still remain challenges to take in pharmacokinetics test, so it was necessary to optimize structure of the compound in order to apply it to clinical trials.

In the process of advancing his research on optimizing structure of TM5007 as a lead compound, Dr. Miyata succeeded in detecting a lot of highly active compounds with excellent drug-likeness. Selecting TM5275 as a representative compound, Dr. Miyata had confirmed the efficacy of TM5275 using 1) 3 types of thrombosis models of rats to investigate hemorrhage and in vivo antithrombotic action, 2) 1 type of thrombosis model in cynomolgus monkeys (Izuhara Y et al., J Celeb Blood Flow Metab. 2010 May;30:904-12.). On clinical study with comparative control drugs, TM5275 showed positive antithrombotic action equivalent to or better than clopidogrel which is well used as an antithrombotic drug. Noteworthy about the fact was that TM5275 didn’t prolong bleeding time at all compared to comparative drugs in spite of increasing doses. PAI-1 has completely different mechanism from that of traditional drugs which just hamper the process of clot formation, in the way that PAI-1 inhibitor dissolves only clot in the blood vessel. In addition, the pharmacokinetics test has accomplished good result, and it hasn’t showed adverse consequences in preliminary general toxicity test, safety pharmacological study and genetic toxicity test in non-GLP.

PAI-1 inhibitor belongs to the group of thrombolytic drug. However, the drug of this group consists only of injectable protein bio-products so far and orally-available low molecular drug has not been developed. PAI-1 inhibitor has function to protect internal organ and to bleed less, since PAI-1 inhibitor is different from existing antithrombotic drugs in the mechanism. Therefore it is expected to be a treatment and a preventive medicine for wide variety of indications.

Now, we have obtained candidate compounds much better than TM5275 and are working hard to shift them to the clinical development stage.

The results of the phenotypic analysis of genetic disruption of PAI-1 knockout mice, shows that PAI-1 has positive effects for anti-inflammation and stem cell regeneration (see the illustration above). Other than anti-inflammatory effect, we have vigorously practiced research on stem cell regeneration effect, inhibitory effect on immune cell migration and anti-inflammatory effect, targeting kidney. We are aiming for the further expansion of PAI-1's application. In fact, we have found out that there is improvement in blood flow in models of limb ischemia, with the promotion of vascularization by orally-administered PAI-1 (Tashiro Y et al., Blood. 2012 June 28; 119:6382-93., Joint research with Dr. Hattori of Tokyo University).


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