The global fight against infectious diseases, both emerging and re-emerging, continues to persist. Japan’s commitments and reputation as a good global citizen and its responsibility to uphold domestic and international human security mean that it is in Japan’s best interest to leverage its domestic innovation and technology capabilities for global infectious disease prevention and control. The Global Health Innovative Technology Fund (GHIT Fund), an international non-profit organization based in Tokyo, Japan, was established by the Japanese government, multiple Japanese pharmaceutical companies, and the Bill & Melinda Gates Foundation as the first fund of its kind, with an aim to tackle the global burden of infectious diseases by facilitating and funding global health R&D of drugs, vaccines, and diagnostics. Since its inception in 2013, the GHIT Fund has invested more than 60 million USD in more than 60 projects, which consist of collaborations among Japanese and non- Japanese entities, seven of which have already progressed to clinical stage development. Additionally, many Japanese organizations (pharmaceutical companies, universities, and research organizations) have initiated screening activities under the GHIT investment mechanism for the purpose of identifying promising hit compounds for infectious diseases. Six of these projects have progressed to the hit-to-lead phase. Japan will continue to play a major role in the global health arena by further advancing of R&D innovations for infectious diseases.

I would like to share my experience of being part of Prof. Schreiber’s lab over the last 2 years at the Broad Institute of Harvard and MIT. The Broad is a renowned biomedical and genomic research center located in Cambridge, Massachusetts, United States. Through activities in the lab, I learned cutting-edge chemical biology and also discovered the importance of collaborating with diverse teams. To share something specific, Prof. Schreiber recently reported on a new computational tool which enables the mechanism of action for small-molecules to be revealed. This is accomplished by correlating chemical sensitivity and basal gene expression of cancer cell lines. Given the promising results of this study, we are starting to see how big data analysis will allow for the evolution of next generation drug discovery. In fact, the Broad Institute is collaborating with computing infrastructure groups, such as Google genomics, to provide a service to use GATK software via the Google cloud platform for genomic research.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. In recent years, the spread of multi-drug resistant Mtb (MDR-TB) and extensively drug-resistant Mtb (XDR-TB) strains have greatly complicated treatment and reduces successful treatment outcomes. Furthermore, the co-infection of TB and HIV has become a critical issue. In spite of this situation, one of the first anti-TB medications developed in the last 40 years with a novel structure and mechanism of action has the potential to alter the current treatment landscape. Otsuka was interested in the nitroimidazooxazole structure having anti-TB activities as the lead compound, and we expanded mainly a side chain moiety of the second position. We optimized these derivatives by the measurement of in vitro antitubercular activities and the in vivo examination in TB-infected mice. As a result, we found many derivatives having potent in vitro and in vivo activities without mutagenicity, and finally discovered delamanid for the treatment of multi-drug resistant pulmonary tuberculosis.

Interleukin-2 inducible tyrosine kinase (ITK), its signaling pathway plays an important role in the activation and differentiation of T-cells. Therefore, inhibition of ITK is considered to be a novel therapeutic strategy for allergic diseases. Our lead compound was found to be categorized into Type-1 1/2 inhibitor, characterized by DFG-in conformation of the activation loop. Using a back pocket for kinase inhibition is known to improve kinase selectivity profile, despite our lead compound is still not selective enough against lymphocyte-specific protein kinase (LCK) which operates upstream of ITK. So we planned to discover new lead compounds by using FBDD fragment-linking approach while keeping its valuable back pocket binding motif. As a result, we identified the novel ITK Type-1 1/2 inhibitor with making its hinge binding motif smaller and improvement LCK selectivity.

Several CysLT₁ antagonists are widely used in clinical as a therapeutic agent for treating bronchial asthma and allergic rhinitis, because of their high potency and high safety as well. On the other hand, some patients are reported not to respond clinically. It is not known exactly why such nonresponders exist. Nonetheless, several reports say that CysLT₂ receptor, identified as another leukotriene receptor, can involve airways contraction and inflammation. Therefore, we hypothesized that dual CysLT₁ /CysLT₂ antagonists can be more potent and useful therapeutic agents for asthma, and then started drug discovery research from our hit compounds possessing both CysLT₁ and CysLT₂ antagonist activities. After a variety of drug designs and syntheses, we discovered gemilukast (ONO-6950, compound 26) showing potent dual CysLT₁/CysLT₂ antagonist activities. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma. In this report, we describe the development of gemilukast including details of structure-activity relationships and pharmacokinetics evaluations.

Phosphodiesterase 10A (PDE10A), a dual hydrolase of cAMP and cGMP, is highly expressed in striatal medium spiny neurons (MSN). Inhibition of PDE10A modulates the activity of MSN via the regulation of cAMP. Therefore PDE10A inhibitor is expected as a therapeutic method for schizophrenia. We transformed Avanafil (PDE5 inhibitor) derivatives, which had weak inhibitory actinity against PDE10A and discovered stilbene derivatives. More conversion of stilbene to improve the metabolic stability and brain penetration produced dimethylamino pyridimidine compound that attenuated conditioned avoidance responses (CAR) in rats. We performed in-depth optimization, and successfully obtained stilbene compound that was substituted with 3-methyl-7-fluoro quinoxaline substituents, which had reduced genotoxicity, and CYP inhibition.

GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be novel insulin secretagogues with low risk of hypoglycemia. Our derivatizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity, receptor selectivity and pharmacokinetics. As a result, we discovered an orally available insulin secretagogue DS-1558, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl) propanoic acid. The docking study of DS-1558 and hGPR40 receptor could explain the result of SAR study reasonably. This compound docked well to the binding site using binding pockets effectively with the β-ethoxy group and the (R)-indan moiety. DS-1558 was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats and potent glucose-lowering effects during oGTT on ZF rats.

ACS national meeting is one of the biggest conferences for chemistry in the world. This meeting was held in San Diego, CA, from March13 to 17, 2016. There were a number of sessions for computational chemistry, since the meeting theme was “Computers in Chemistry”. Dr. William Jorgensen, who contributed to the development of a binding free energy calculation method (Free Energy Perturbation: FEP), was invited as a plenary session speaker. Topics regarding FEP methods, ITC data interpretation, and FolditDD project will be reported.