The Drug Discovery Support Network was established for seamless support to academia-based drug discovery. Department of Innovative Drug Discovery and Development at Japan Agency for Medical Research and Development (AMED) functions as the headquarter of the Network. Drug Discovery booster, our core initiative, includes planning of strategies for research and IP (intellectual property), technical support and advice for licensing-out etc. So far more than 30 drug discovery seeds were selected as booster projects. Our coordinators and PI take a co-leadership role in the projects. We plan to start a new public-private partnership initiative bridging innovative academia seeds and unique compounds from pharmaceutical companies and advanced screening technologies.

Under the environment of regulatory restriction, lack of new molecular target finding, increasing drug development cost and decreasing the success ratio for launch, Lilly has been ready for making the strategy/tactics how to cope with the patent expiration of our 3 (three) blockbuster drugs. By the effective use of the advice from external consultant, in addition to the wisdom of our internal scientists, Lilly decided to collaborate with external parties in an attempt to use their knowledge and wisdom as the key word of `open innovation partnership' ahead of other multi-national companies. Taking this opportunity, I would like to explain the function of 1. Global External R&D 2. Open innovation drug discovery.

The leading-edge Sciences such as chemistry, biology, medicine and physics are extremely important for the research of drug discovery without doubt. It takes a long time to complete R&D of drug discovery having high risk. Something important other than theory is sometimes thought to be necessary to overcome various problems encountered on the occasion of R&D. I would like to highlight the something important through the R&D stories of JT original new drugs, elvitegravir and trametinib with episode.

Thermosensitive TRP channels such as TRPV1 and TRPM8 are implicated in pain. Voacangine is an iboga-type indole alkaloid in Voacanga africana, an apocynaceous plant which is used as traditional medicine in Africa. It was found that voacangine possessed antagonistic activities against TRPV1 or TRPM8 channels and was the first stimulus-selective TRPM8 antagonist. To investigate SAR, total syntheses of voacangine-related new alkaloids were done. A SAR study using voacangine and its related compounds on TRP channels antagonistic activities showed that catharanthine and dihydrocatharantine were potent TRPM8 antagonist and isoquinuclidine part having the same absolute configuration with voacangine was essential for chemical agonist-selective TRPM8 inhibition.

Mineralocorticoid receptor (MR) antagonist are a clinically proven drug class for the treatment of hypertension and related heart failure. However, these drugs are prescribed with specific care of hyperkalemia, which has resulted in limited clinical use. We designed novel biphenyl derivatives to have both selective MR antagonistic activity and carbonic anhydrase (CA) inhibitory activity, and then found that our biphenyl derivatives show anti-hypertensive activity with lower hyperkalemia risk. Further improvement in pharmacokinetic properties of these derivatives led to the compound that showed remarkable in vivo efficacy in the animal models of hypertension with lower hyperkalemia risk than spironolactone.

The five G-protein-coupled muscarinic acetylcholine receptors (mAChR) utilize acetylcholine as their endogeneous agonist and are broadly distributed where they regulate a diverse array of physiological processes. We elected to pursue the discovery and development of selective M₅ NAMs and PAMs to enable the dissection of the physiological role and therapeutic potential of M₅ modulation. A functional high throughput screen identified both acetylcholine receptor antagonist and agonist selective for the M₅ subtype. Application of rapid analog, iterative parallel synthesis efficiently optimized both compounds to arrive at most potent M₅ NAM and PAM prepared to data and provided tool compounds, NAM was demonstrating excellent multispecies PK, high CNS penetration、 and enantiospecific inhibition and PAM was demonstrating modest CNS penetration.

FGFRs belong to the family of receptor tyrosine kinase that regulates multiple biological processes, such as cell proliferation and migration. Various genetic alterations as well as overexpression of FGFRs in a subset of tumors have been reported, and these genetic alterations are suggested to be associated with tumor growth and survival. We have discovered an orally available and selective inhibitor of FGFR1, 2, and 3, named CH5183284/Debio 1347. The hit compound was identified from our original compound library by a high throughput screening program. Chemical modifications utilizing 3D-modeling analyses of the hit compound and its derivatives with FGFR1 were mainly aimed at enhancing activity that was selective to FGFRs. CH5183284/Debio 1347 showed antitumor activity against cancer cell lines with genetic alterations in FGFRs both in vitro and in vivo in xenograft mice models.

The Division of Medicinal Chemistry of The Pharmaceutical Society of Japan started "The nurture project of an innovative drug development researcher" in 2012 to contribute to social and educational activities related to innovative drug development more positively. This project is carried out with the cooperation of pharmaceutical industries supporting our activities as the corporative members of the division. Expert researchers in a pharmaceutical industry visit university and give lectures based on their knowledge and experience in the field of drug development using the case histories of drug discovery, targeting students aiming to be engaged in drug research and development in the future. To have direct contact with and be taught by industrial researchers will convey the importance and charm of drug research and development to such students, which will not be realized by studying with textbooks. Such lectures will surely help nurture their spirits of and enthusiasm for drug development. In 2015, this project entered the fourth year. The achievements of the project in the last 3 years and the summary of the questionnaire survey carried out at the end of 2014 are reported.