Mitsubishi Tanabe Pharma Corporation (MTPC) was born in October 2007 through a merger between Tanabe Seiyaku Co., Ltd. and Mitsubishi Pharma Corporation, from which time it has created highly original drug products, including Imusera^® for multiple sclerosis as well as Tenelia^® and Canaglu^® for Type 2 diabetes. MTPC is actively engaged in drug discovery in new disease areas using a comprehensive approach that responds fluidly to environmental changes in regulation, industry, and related scientific fields. This needs-based approach to discovery first identifies a target disease, analysis of which forms the basis for target molecule selection. Target molecule characteristics in turn drive selection of discovery modalities, after which non-clinical and clinical studies are combined in a manner that both improves success rates and streamlines nonclinical evaluation. MTPC is focused on transforming drug discovery paradigms, such as by leveraging target validation and biomarker searches while also incorporating clinical research to traverse the “valley of death” of drug discovery.

The field of medicinal chemistry is facing increasing challenges as biologics look to gain momentum over small molecule drugs in the pharmaceutical market. What can we, the medicinal chemists, do to revitalize our field? The author wishes to share his insights gained through his drug discovery research experience in both industrial and academic sectors.

Dolutegravir is the next generation HIV-1 integrase strand transfer inhibitor which maintains potent activity against first generation integrase inhibitor resistant mutants and shows high genetic barrier to resistance. The superior resistance profile is supported by dolutegravir’s long dissociative half-life from intasome (integrase enzyme and viral DNA nucleoprotein complex). Furthermore, according to structural analyses based on recent x-ray studies on intasome-ligand binding complex, dolutegravir shows tight π-stacking interactions with the cytosine base and the adenine base conserved at the 3’end of viral DNA as well as binding to the active site metal cofactors. On the other hand limited interaction with integrase amino acids was observed in dolutegravir complex, suggesting being tolerable to amino acid mutations.

Selective SGLT2 inhibitors have recently been shown to enhance urinary glucose excretion and reduce hyperglycemia in patients with Type 2 diabetes mellitus (T2DM). SGLT2 inhibitors could increase the caloric output in urine due to the urinary glucose excretion, suggesting that SGLT2 inhibitors do not result in the weight gain often seen with other antihyperglycemic agents currently prescribed, making them an even more expected candidate for next-generation of antidiabetic agents.We describe the C-glucoside derivatives containing azulene ring or heteroaromatics as SGLT2 inhibitors. A number of compounds were synthesized and evaluated, including SAR studies, which culminated in the discovery of a novel selective SGLT2 inhibitor ipragliflozin (ASP1941), which exhibits properties warranting a clinical development for the treatment of T2DM. On January, 2014, ipragliflozin was approved as the first selective SGLT2 inhibitor for a treatment of T2DM in Japan.

Lysine-specific demethylase (LSD1), which is highly expressed in various cancer cells and involved in the proliferation of the cancer cells, is of interest not only as a biomarker of cancer but also as a molecular target for anticancer drug. Here, we report our research on drug delivery molecules based on LSD1 inhibition, focusing on the mechanism of LSD1 inhibition of trans-2-phenylcyclopropylamine (PCPA). We designed and synthesized the drug delivery-type LSD1 inactivators consisting lysine moiety as a carrier of PCPA. As a result, some of them strongly and selectively inhibited LSD1 and proliferation of cancer cells. Furthermore, we designed LSD1-inhibition triggered PCPA-drug conjugate as drug delivery molecule targeting cancer cells overexpressing LSD1. In a proof of concept study, a PCPA-tamoxifen conjugate released 4-hydroxytamoxifen, an active metabolite of tamoxifen, dependently on LSD1 and showed selective antiproliferative effect on cancer cells.

Orexins are a family of neuropeptides that regulate sleep/wakefulness and feeding behavior, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy, diabetes, and obesity. While a large number of orexin receptor antagonists have been developed, there was no report of a potent non-peptidic agonist, which showed in vivo efficacy. Motivated by these observations, we initiated an effort to discover and optimize non-peptide orexin receptor agonists. High throughput screening (HTS) of the chemical library at University of Texas Southwestern identified hit sulfonamide compounds and our efforts to optimize the hit compounds to some lead compounds led to a potent OX2R-selective agonist YNT-185 (OX2R: EC₅₀ = 28 nM, OX1R/OX2R= 100). Intracerebroventricular (icv) and interperitoneal (ip) administation of YNT-185 · 2HCl in the light phase showed elongation of period alertness in C57BL/6J mice in a dose-dependent manner. Also, the icv and ip injection of the compound attenuated the SOREM (Sleep Onset Rapid Eye Movement) of narcoleptic symptoms in narcolepsy murine model mice.

In recent years, the number of elderly people in Japan is increasing. As a result, the number of patients with dementia are also increasing rapidly. Alzheimer’s disease, Vascular dementia, Dementia with Lewy bodies and Frontotemporal dementia accounts for approximately 90% of overall dementia. Therefore, they are regarded as four major dementia. Many kinds of dementia have olfactory dysfunction because pathological changes occurs in the sense of smell-related domain. However, most of patients don’t complain for olfactory dysfunction. The reason is because progression is generally slow. As a result, patients are not awareness. In addition, early detection is extremely difficult because patients have cognitive disorders. However, the olfactory nerve system has ability to regenerate and can stimulate cerebral limbic system directly. We expect that early intervention for olfactory dysfunction can improve cognitive function and prevent the progress of dementia.

The 2nd International Symposium for Medicinal Sciences was held on March 28th at Pacifico Yokohama as a part of the 136th Annual Meeting of the Pharmaceutical Society of Japan. The objectives of this symposium are to encourage pharmaceutical company researchers and also to create an important international platform for all those interested in the medicinal sciences. Two Plenary Lectures [Dr. Michael J. Sofia (Arbutus Biopharma, Inc.), Professor Craig W. Lindsley (University of Vanderbilt, Division of Vanderbilt Center for Neuroscience Drug Discovery)] were given, and there were 36 Invited Poster Presentations (27 presentations from domestic and 9 presentations from foreign countries). This symposium covered a wide variety of the drug discovery fields, structure activity relationship, natural product chemistry, molecular biology, clinical research, etc.