News Release

Yamanouchi Pharmaceutical Co., Ltd.

Yamanouchi Discovers Three New Target Genes for Drug Screening in Cooperation with Metabolex
- Accelerating Discovery of New Compounds in The Field of Diabetes and Obesity-

March 18, 2003

 Tokyo, Japan - March 18, 2003 - Yamanouchi Pharmaceutical Co., Ltd. (President: Toichi Takenaka) announced that it has discovered and identified three targets for drug screening in its cooperative research program with Metabolex, Inc. (President and Chief Executive Officer: Harold Van Wart, Ph.D.), CA, USA in the field of type 2 diabetes (insulin-resistant diabetes with impaired glucose tolerance) and obesity. These new targets were discovered in less than one year since the joint research program was started on a full scale.

The three targets discovered and identified include a membrane receptor, a functional protein, and a metabolic enzyme, and are all new target genes for drug discovery in the field of diabetes and obesity. Joint research results obtained to date have functionally verified that controlling these genes is useful for treating diabetes and obesity. It was discovered from Metabolex' proprietary human genome database containing DNA chip analysis data that the amount of the genes expressed for both the membrane receptor and the intrinsic ligand*1 which binds to the receptor is significantly increased in patients with type 2 diabetes caused by the impairment of insulin function. Studies also showed that insulin resistance is improved as the amount of the gene's intrinsic ligand or the receptor is increased. These findings indicate that intracellular signals (information transmission) mediated by the gene's receptors enhance insulin's functions and that the expression of these genes increases in order to make up for decreases in insulin function due to decreases in the intrinsic ligand and/or receptors in type 2 diabetes patients. Therefore, a compound that binds with the receptors to make up for decreases in intrinsic ligand and inhibits the expression of increases genes as a result may become an effective drug for diabetes with a new mechanism of action. Function verification experiments showed that the two other genes are also promising as targets for the discovery of drugs for type 2 diabetes.

Yamanouchi plans to use these three genes as targets and start screening low-molecular-weight compounds that control their activity from its own library in order to accelerate the development of new drugs useful for diabetes and obesity. At present, new function verification experiments are underway in order to verify the usefulness of some more genes that may serve as targets for new drug development. In the joint research program with Metabolex, Yamanouchi intends to identify candidate compounds from at least 10 targets.

Yamanouchi gives a great strategic importance to genomic drug discovery and is promoting genomic drug discovery through 3 avenues (triangle approach): the gene-to-disease approach based on information on genes, the disease-to-gene approach based on information on diseases, and the compound-to-gene approach based on information on compounds. It is enthusiastically engaged in strategic alliances with research institutes and venture companies in Japan and abroad. As one of the strategic alliances, Yamanouchi signed a 3-year cooperative research agreement in March 2003 with Metabolex in the field of diabetes and obesity, which is one of the major fields for drug discovery research at Yamanouchi. Metabolex has spearhead technology in this field. Yamanouchi plans to use its Tsukuba Research Center as the hub in an effort to swiftly propel multifaceted drug discovery programs in order to win the ever-intensifying global genomics drug discovery race.

*1: Receptors and intrinsic ligands

Receptors are proteins that transmit extracellular information to cells. Originated in the organism, intrinsic ligands transmit specific information to cells when they specifically bind to receptors. The relationship between the ligand and receptor is like the relationship between the key and key hole.

Insulin's effect
Reference 1: About Metabolex

Established in 1992, Metabolex is a bioventure company specializing in the screening and development of antidiabetic drugs. It screens genes related to the development and progression of diabetes and obesity and analyzes their function using its advanced knowledge and genomic technology and one of the world's largest gene expression databases it has constructed over years in the field of diabetes. It is a bioventure company with one of the most comprehensive and versatile research programs in the field of diabetology. It already collaborates with US giants such as Pfizer and Abbott. Yamanouchi is the first Japanese company that Metabolex has tied up with.

Reference 2: About type 2 diabetes

Secreted by pancreatic beta-cells, insulin constantly controls blood glucose levels by regulating sugar and fat metabolism in the body. Blood glucose rises when the secretion of insulin is impaired or its effect is inhibited (hyperglycemia). High blood glucose levels aggravate vascular lesions when they persist over a long period of time (diabetes), leading to the development of arteriosclerosis, myocardial infarction, cerebral infarction, nephropathy, retinopathy, and neurosis. There are two types of diabetes: types 1 and 2. Type 1 diabetes is caused when insulin becomes deficient as a result of beta-cell destruction. However, diabetes is type 2 in the great majority of patients. Insulin is normally secreted in these patients but does not function normally for some reason, and blood glucose levels rise. In Japan, more than 95% of patients have type 2 diabetes. According to a survey conducted by the Japanese Ministry of Health and Welfare in the fall of 1997, the number of patients with type 2 diabetes in Japan was estimated to be 6.9 million, or one out of 10 adults. Changes in lifestyle such as eating habits and lack of exercise, obesity, and stress are believed to be major factors that contribute to its onset. The number of patients and those on the borderline has been rapidly increasing in recent years. At present, it is estimated to be about 13.7 million, including young adults and children. This number is showing a tendency to further increase.