Sumitomo-Dainippon Pharma Co., Ltd. is a research and development （R&D）-based pharmaceutical company that has been established in October 2005 by the merger of former Dainippon Pharmaceuticals and former Sumitomo Pharmaceuticals. It has grown into a global company with sales of approximately 500 billion yen. One of three research focus areas aiming to become global leader in our Mid-Term Business Plan 2022, “Psychiatry and Neurology” is known as an area where new drug development is difficult, and many companies have withdrawn. However, we have launched a number of new drugs, and our long-term R&D experience is a great strength of our company, so we are energetically conducting drug discovery research to create innovative new drugs in this area which have high unmet medical needs. This column introduces our drug discovery research strategy, organization, measures such as research project system, application of cutting-edge technologies, and open innovation initiatives, centering on our Drug Research Division （RD） in charge of drug discovery research in the field of Psychiatry and Neurology.

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In 2007, I embarked on my academic career at the newly established chemistry department at Nanyang Technological University Singapore and since then, about 14 years just flew past me. During that period, I have been engaged in research and education as an organic chemist and also in the University management as a Head of Department and a chairman in the chemistry and chemical engineering committee of the NTU Research Council. This essay describes recent topics on research and education in NTU and Singapore especially from the view points of my research areas （synthetic organic chemistry）.

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The circadian clock is a biological system ubiquitous to almost all organisms on the earth, and controls daily rhythms in our body. Many physiological functions are rhythmically regulated by the cycles of expression, post-translational modification, and degradation of the clock proteins constituting the circadian clock. Disruption of circadian rhythms due to shift work and social jet lag is getting worse in modern society, and has been related with not only sleep disorders, but also various diseases, such as cancer and metabolic disorders. Small-molecule compounds targeting the clock-related proteins will provide a useful tool for uncovering the molecular mechanisms of circadian-related diseases and their treatments. In this article, we introduce the unique circadian clock modulating compounds and their potential for drug discovery.

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Atopic dermatitis is a chronic inflammatory skin disease due to aberrant immunological reactions as one of the leading etiologies. Topical steroids and tacrolimus ointment, which are standard therapeutic agents, have side effects such as skin thinning and irritation. Therefore, there is an urgent medical need to develop new safety therapeutic agents. Janus kinases （JAK1, JAK2, JAK3, Tyk2） are intracellular tyrosine kinases, play critical role in intracellular signal transduction, and have drawn significant attention as attractive therapeutic target for autoimmune inflammatory diseases. We conducted to develop a novel JAK3 inhibitor for new immunomodulator. Regarding SAR exploration, to be obtain high kinase selectively, we considered and investigated three-dimensionality in the compound. As the result, we succeeded in discovery of delgocitinib bearing spiro scaffold, which showed high JAK3 inhibitory activity and high kinase selectivity. Delgocitinib ointment received manufacturing and marketing approval in Japan as the world's first topical JAK inhibitor for the treatment of atopic dermatitis.

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The threat of carbapenem resistant Gram-negative pathogens e.g. Enterobacterales, P. aeruginosa and A. baumannii is expanding worldwide. One strategy to discover a new antibacterial to be active against these resistant pathogens is to utilize the bacterial iron acquisition system by attaching a siderophore-mimicking molecule to the parent molecule. In 1980’s, our team identified a siderophore cephalosporin A-2, which displayed a potent activity against P. aeruginosa. We restarted the SAR study of siderophore cephalosporin to increase the in vitro and in vivo antimicrobial activity against various carbapenemase-producing resistant strains by the modification of the C-3 and C-7 side chains of A-2. Here, we report the SAR results about the several siderophore cephalosporins that led to the discovery of Cefiderocol.

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Photoimmuno therapy （PIT） is a new molecular-targeted phototherapy in which an antibody conjugated with IR700 （Ab- IR700）, a phthalocyanine derivative, is administered followed by irradiation with near-infrared light. PIT causes cell death due to cell membrane damage, and the formation of aggregates of Ab-IR700 on the cell membrane by photochemical reactions is an important mechanism of cell killing. It has also been shown that the formation of radical anion of IR700 and its protonation are necessary for the progress of this photochemical reaction. In this article, the characteristics and therapeutic mechanisms of PIT will be reviewed, and in particular, our recent findings on photochemistry will be presented for future drug development.

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In recent years, the progress of continuous manufacturing utilizing flow technology at API production has been remarkable. National projects have contributed significantly to the development of them for example, Novartis-MIT Project（USA）, F3 Factory（EU）, iFactory（JP）. On the other hand, in the field of drug discovery, the current situation is that flow technologies are not widely used because of a feeling of resistance to new technologies by researchers. In that case, I think that we should find the utilization of flow technologies in drug discovery assuming the exit for continuous manufacturing. This paper describes the direction of utilization of flow technologies in drug discovery with an eye on continuous manufacturing.

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As a Japanese member of Editorial Advisory Board of J. Med. Chem., I encourage Japanese medicinal chemists to submit manuscripts actively to J. Med. Chem. Because J. Med. Chem. is the top journal in medicinal chemistry, there are lots of merits to publish papers in the journal, which are distributed to a great number of medicinal chemists around world. The process for paper publication in the leading journal J. Med. Chem., i.e., preparation of a manuscript, submission, and response to the review, is a really hard but challenging work. However, the experience of successfully publishing a paper in the journal effectively trains the author as a medicinal chemist. Thus, extensive publication of excellent papers in J. Med. Chem. from Japan are very profitable for advancing medicinal chemistry as well as drug development in Japanese academia and industry.

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