In order to continually create high-value medical solutions for society and patients, it is essential to utilize the advancement of cutting-edge science for drug discovery research, and to have an appropriate mechanism to realize this goal. At Astellas Pharma Inc., we encompass various kinds of scientific progress as opportunities for the creation of new drugs and are continually challenging to drug discovery research from a multiple approach perspective, considering the three elements of “disease”, “biology”, and “modality & technology”. In addition, we define Focus Areas from these three elements and implement drug discovery research by expanding and redefining our Focus Areas. Our internal HR system to promote innovation creation is also very important. In this paper, I would like to share ideas about the traits of the innovative drug discovery researchers of the future.

National Cancer Center (NCC) has recently developed a novel framework between hospitals and research institute (Tsukiji Translational Research Board: TTRB), and an organization in research institute (Fundamental Innovative Oncology Core: FIOC) to promote translational research (TR) and reverse TR (rTR) at Tsukiji campus in cooperation with pharmaceutical companies and academia. TTRB provides one stop service about consultation of research design and responsible researchers, and pharmaceutical companies can much easily access to relevant departments in hospitals and research institute. The direction of TR/rTR plan is rapidly determined by TTRB, which is communicated to FIOC. FIOC actually performs TR/rTR and supports the development of novel biomarkers and drugs, and pharmaceutical companies can easily reach clinical samples with detailed clinical information, original research findings, advanced and standard technologies and deep discussion with many experts in NCC reseach institute. During recent 16 months, already 20 TR/rTR studies have been conducted by TTRB, and hereafter this approach will increase more.

I had been worked in Kishi group at Harvard University as a postdoc researcher. In Kishi group, we had engaged in total synthesis of halichondrins, which is a family of natural products possessing highly potent anti-tumor activities. I would like to share my experience in Kishi group and also my personal opinion on a future of Natural Product Synthesis.

Japan has been enjoying its unique health insurance system, under which almost every drug is covered, for over a half century. Only efficacies and safeties were considered during decision making process of approval/reimbursement and there were no room for consideration of efficiency, or cost-effectiveness. However, due to the rapid growth of total healthcare expenditure, there has been growing concern about the sustainability of our health care system. Government tried to implement health economic evaluation data (HTA data) into public health care system. It was introduced in 2016 as the pilot phase and will entirely be done in 2019. Unlike other countries which already introduced HTA systems, Japan would use HTA data for price revision of existing drugs. To upgrade our healthcare/HTA system, the role of appraisal, in which various issues other than the cost-effectiveness are considered, should be reconsidered. Health economic data should be used as a tool which can upgrade the value of new products and persuade various stakeholders who are anxious about the financial burden.

The orexin receptors, two distinct G-protein coupled receptors (OX1R, OX2R) widely expressed in the brain, play a central role in the regulation of sleep and wakefulness. OX1R and OX2R exert their functions through the binding of endogenous neuropeptides orexin-A (hypocretin-1) and orexin-B (hypocretin-2) which are produced in the hypothalamus. Due to the therapeutic potential of modulating these receptors, it has been an active research area for the treatment of disorders associated with sleep/awake state control. Our original investigational drug, lemborexant, is a novel and potent dual orexin receptor antagonist derived from a unique tri-substituted cyclopropane chemical series, and the submission of the NDA and J-NDA for insomnia disorder treatment were achieved in Dec 2018 and Mar 2019, respectively. Moreover, a clinical trial for ISWRD (Irregular Sleep-Wake Rhythm Disorder) in Alzheimer dementia subjects is also ongoing. The drug discovery of lemborexant was already reported in the August 2018 issue, however, in this article we would like to elaborate on different details for the occasion of the Breakthrough Award, Division of Medicinal Chemistry, PSJ.

Influenza is an acute respiratory disease caused by infection with an influenza virus. Currently available anti-influenza drugs are neuraminidase inhibitors suppressing virus budding and release from a cell. However, there are still unmet needs for new anti-influenza drugs with better efficacy and safety profile, and activity against resistant strains and highly pathogenic strains. Cap-dependent endonuclease (CEN) is an essential metalloenzyme for viral replication and has two metal-ions in the active site. Therefore, we selected compound 1 as a hit compound possible to bind to the active site and started a structure activity relationship study. An active form of Baloxavir Marboxil exhibited broad and potent antiviral activity against various influenza virus. In mice models, Baloxavir Marboxil (a prodrug form) has demonstrated more pronounced than Oceltamivir. In this paper, we will describe how we successfully discovered a novel and orally active CEN inhibitor, Baloxavir Marboxil and its non-clinical profile.

ABHD12 is a major enzyme that metabolizes lysophosphatidylserine (lyso-PS), a class of immunomodulatory lipids that has been shown to regulate functions of immune cells. Our understanding of the physiological functions of ABHD12 has been limited by a lack of selective and in vivo-active ABHD12 inhibitors. In this study, we set out to investigate the physiological functions of ABHD12 by using selective chemical probes for ABHD12. We have identified a selective and in vivo active ABHD12 inhibitor DO 264 as well as a structurally related inactive control probe (S)-DO 271 after a compound library screening and the lead optimization. DO 264 dose-dependently elevated the lyso-PS content of macrophages and the mice brain. We also found the macrophages and the mice treated with DO 264 showed augmented immune responses. These results support an immunostimulatory function for the ABHD12-(lyso)-PS pathway that can be pharmacologically controlled with selective ABHD12 inhibitors.

Pharmacological inhibition of BACE1 has received considerable attention as a potential disease-modifying treatment for Alzheimer’s disease. Inhibition of BACE2, a close homologue of BACE1, causes depigmentation in animal models, whereas its overall physiological function remains largely unknown. To avoid potential side-effects arising from BACE2 inhibition, we initiated medicinal chemistry efforts to explore selective BACE1 inhibitors over BACE2. Comparative analysis of nonselective verubecestat bound to BACE1 and BACE2 revealed that the water network in the S2’ pocket is different between BACE1 and BACE2, indicating that utilizing this network might increase selectivity. Our SAR efforts targeting the water network culminated in propynyloxazine 7 with 107-fold selectivity over BACE2. Indeed, the cocrystal structures of an analogue of 7 bound to both enzymes confirm disruption of the water network in both cocrystal structures. These results suggested that targeting the water network could aid structure-based discovery of BACE1 selective inhibitors over BACE2.

We attended the 25^th EFMC international Symposium on Medicinal Chemistry (EFMC-ISMC 2018) which was held in Ljubljana, Slovenia from 2 to 6, September, 2018. This symposium is one of the biggest symposiums in the field of medicinal chemistry. Therefore, many medicinal chemists from both pharmaceutical company and academia were attending. This report describes the summary of the symposium and highlights selected topics from the First Time Disclosure session.