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Ascertaining the absorption, distribution, metabolism, and excretion (ADME) profile of drugs is one of the most crucial factors in the process of drug discovery. Since it is important to combine water solubility and cell permeability within the compound to achieve the desired ADME properties, an appropriate balance between lipophilicity and hydrophilicity is required. It is often necessary to facilitate hydrophilicity of very hydrophobic candidates, because quite lipophobic molecules are rarely hit as positive in molecular-targeted or cell-based screenings. For that purpose, it has been popular to conjugate hydrophobic molecules with polyethylene glycol (PEG). However, PEG is a polymer, and PEG-conjugated molecules are not uniform. Besides, the dosage should be much increased compared with the original molecule due to the increase in molecular weight. Therefore we have been developing alternative ways to endow hydrophobic compounds with extra hydrophilicity by conjugating with symmetrically branched glycerol oligomers. This technology is versatile and easily applicable to various hydrophobic compounds. Water-solubility of fenofibrate, one of the most hydrophobic medicines in clinical use, was facilitated by a factor of more than 2000, and its lipid-lowering effect in vivo improved more than ten-fold, by simply conjugating with branched glycerol trimer, for instance. Here we will briefly introduce the basic concepts and our successful experiences of applying branched glycerol oligomers including antitumor agents in terms of water-solubility, pharmacological effects, and pharmacokinetics, and merits and current issues will be discussed in this review.

Sudachi (Citrus Sudachi) is a sour fruit and is a popular seasoning for Japanese dishes, Washoku. It can grow only in Tokushima and the surrounding areas for some reason, and therefore, Sudachi is a specialty of Tokushima prefecture in Japan. We usually use only its juice, and the size of the fruit is so small that a huge amount of pomace has been an industrial problem of the region. Therefore, we undertook exploratory studies of the Sudachi peel in terms of health promotion with making a kind of collaborative consortium for the study of acid citruses. Our recent activities on Sudachi research including the consortium were shared and discussed in the symposium, and the metabolic effects of Sudachi peel will be briefly introduced in the current manuscript.

Physical exercise is well known to be beneficial to our health. Therapeutic exercise is widely applicable to metabolic disorders, including obesity and diabetes. In addition, recent studies have suggested its potential benefit in the treatment of more various diseases such as mental disorders and cancer. 5'AMP-activated protein kinase (AMPK), which is an intracellular central metabolic sensor as well as a regulator, has been demonstrated to play significant roles in the contracting skeletal muscles, suggesting that AMPK should be one of the key molecules mediating metabolic effects during physical exercise. Therefore, AMPK is a desirable therapeutic target for drug discovery. In the symposium S41 held in the 137th Annual Meeting of the Pharmaceutical Society of Japan, our data on the molecular mechanisms of isoform-specific postprandial suppression of AMPK activity were shared, and we discussed potential roles of AMPK as an intersection where metabolic signals by physical exercise and feeding status crosstalk. Here, I would like to introduce basic knowledge related to AMPK and recent findings regarding how AMPK activity is regulated in response to physiological and pharmacological stimulation.

Sodium-glucose transporter (SGLT)-2 inhibitors, which are currently in clinical use in most of the world, are unique as their hypoglycemic effects are completely independent of insulin action. Potential benefits and indications for the treatment of other diseases like circulatory and renal disorders are attracting attention. SGLT2 inhibitors not only reduce blood glucose levels but also alter the whole-body energy balance to lower body weight, which should result in the amelioration of multiple metabolic disorders like metabolic syndrome. In the symposium, we briefly introduced the physiological as well as biological functions of SGLTs and discussed strategies for drug design by looking back at the history of drug discovery for SGLT2 inhibitors. We also shared our recent data on their combined usage with other hypoglycemic agents and effects on glucagon secretion, which are current clinical topics relevant to SGLT2 inhibitors. Among those topics, strategies for drug discovery of SGLT2 inhibitors are discussed in this review.

The number of patients with metabolic disorders is dramatically increasing all over the world. The diseases often exhibit multiple metabolic disturbances including diabetes, hyperlipidemia, and obesity, and so on, recognized as a concept of metabolic syndrome. It is important to consider the common underlying pathophysiological bases of such metabolic diseases at the suggestion of the teachings of a parable, "The blind men and an elephant," whereby each blind man investigates a different part of the elephant. The lesson could even be applicable to each aspect of the disorders. Physical exercise as well as dietetics harbor versatile preventive and therapeutic potency against diverse metabolic diseases. Thus further investigation into molecular and physiological mechanisms underlying beneficial effects of therapeutic exercise and diet will provide us with significant clues to the elephant behind the disorders. Moreover, it could be of great benefit if such non-drug treatments, which may be hard to achieve for most patients, were replaced with medication. Recently, we demonstrated evidence that activators of 5'AMP-activated protein kinase (AMPK) could be satisfactory exercise mimetics in terms of metabolome. In this review, metabolomic analysis on the significant roles of AMPK in contracting skeletal muscles is described. In addition, our novel prodrug strategy providing extremely hydrophobic agents with marked hydrophilicity by conjugation with branched glycerol oligomers, which can be widely applicable in general to drug design for good pharmacokinetic properties in drug discovery, is introduced.