Eisai has commenced new medium-term business plan EWAY 2025 in fiscal 2016 with looking ahead to the future environmental changes around pharmaceutical industry in the next 10 years. Accordingly, Research & Development structure has been transformed as Medicine Creation, with determining “Neurology” and “Oncology” as the strategically important areas to continuously make innovation, by introducing novel concept “Ricchi”, areas where we can become a front-runner. In addition, we also make efforts on ICT-driven innovation in digital technology explosion, as well as global health in order to fulfill our responsibilities to eliminate tropical diseases in emerging and developing countries so that we can realize human health care philosophy in the world.

It is noteworthy that IT companies as well as many startup companies based in Silicon Valley have made remarkable growth and success within a decade. Stanford University is one of the top private research universities in US college rankings. The university has also played a crucial role in Silicon Valley’s success by providing outstanding engineers and programmers. While universities have struggled to survive in Japan, what makes Stanford so successful in terms of finance and research? In this column, the author would like to discuss the following: relationship between Silicon Valley and Stanford University, Stanford Sleep Research Center, and structural differences in research environments between the US and Japan.

Trametinib is a highly potent, highly selective allosteric inhibitor of MEK1/2. However, trametinib was not discovered from pursuing MEK inhibitory activities. A lead compound was identified by a cell-based phenotypic high-throughput screening to identify those compounds that increase p15^INK4b. Our synthetic efforts were directed at improving antiproliferative activity against cancer cells as well as various other drug properties. These efforts led to the discovery of highly potent and selective MEK inhibitors. Although the molecular target of trametinib was still unknown until the time that trametinib was synthesized, a chemical biological technique revealed that MEK1/MEK2 were the binding proteins of trametinib. We selected trametinib DMSO for development as the first FDA approved drug of this solvate.

Acyl CoA: monoacylglycerol acyltransferase-2 （MGAT2）, which is one of the acyltransferases involved in triacylglycerol （TG） resynthesis in the small intestine, has attracted interest as a new target for the treatment of obesity and metabolic diseases. Lead generation and optimization studies of N-phenylindoline-5-sulfonamide derivatives were conducted with the aim of identifying novel small molecule MGAT2 inhibitors. Consequently, we discovered a potent and selective MGAT2 inhibitor with excellent ADME-Tox profiles and good oral bioavailability. In a mouse oral fat tolerance test, compound 23 effectively suppressed the elevation of plasma TG levels after oral administration at the dose of 1 mg/kg. In this article, we describe molecular design, synthesis, ADME-Tox profiles and biological activities of MGAT2 inhibitors, focusing on an improvement of time-dependent inhibition of CYP3A4 and an avoidance of phototoxicity based on HOMO-LUMO gap hypothesis.

Lysophosphatidic acid （LPA） is a class of bioactive phospholipids which exerts a wide range of physiological and pathophysiological responses. These biological effects of LPA are mediated through G protein-coupled receptors. Six LPA receptors（LPA1-6） have been identified and characterized so far. Of which, we have found that LPA induces the contraction of the urethra via LPA1 receptor. The potency of urethral contraction by LPA is almost the same as by phenylephrine which is a well-known α1 adrenoceptor agonist. Therefore LPA1 antagonist is expected to be a remedy of urination disorder. To obtain a good starting point, high throughput screening campaign against LPA1 receptor expressed CHO cells was conducted and identified a hit compound. Hit to lead optimization efforts to improve in vitro potency using LPA1 receptor expressed CHO cells to give a lead compound ONO-7300243. ONO-7300243 has reduced intraurethral pressure（IUP） in rat as the same efficacy as the α1 adrenoceptor antagonist tamsulosin, which is used in clinical practice to treat dysuria with benign prostatic hyperplasia （BPH）. In contrast to tamsulosin, ONO-7300243 had no impact on the mean blood pressure. These results suggest that LPA1 antagonists could be used to treat BPH without affecting the blood pressure. The improvement of in vivo potency against LPA-induced rat IUP increase model was achieved by scaffold hopping to an alcohol template. The incorporation of pyrrole and indane structure gave to an optimized compound ONO-0300302 which is expected to be a once daily dosing regimen. Binding experiment using［³H］₂-ONO-0300302 and wash out experiment has revealed that this compound possesses a slow tight binding property which leads to the excellent in vivo efficacy.

Parathyroid hormone（PTH）is a polypeptide with 84 amino acids that plays a critical role in calcium homeostasis in human through the binding to PTH type 1 receptor（PTHR1）, as a class B GPCR. Human PTH（1–34）and human PTH（1–84）are clinically used as therapeutic agents for the treatment of osteoporosis and/or hypoparathyroidism, but these peptides need to be injected subcutaneously. To improve the QOL of patients, we started research to discover novel orally bioavailable small molecule PTHR1 agonists. From a High-throughput screening（HTS）, only one spiro-imidazolone scaffold was identified as a hit compound. The structural optimization of the hit led to the discovery of novel orally bioavailable clinical candidate, PCO371. Here we describe the synthesis, SAR, avoidance of reactive metabolite, and in vivo activity of novel spiro-imidazolone derivatives.

Th 17 cells were identified as a third subset of T helper cells and suggested to play a central role in the various autoimmune diseases such as psoriasis and rheumatoid arthritis. The RAR-related orphan receptor gamma（RORγ）is an orphan nuclear receptor expressed in Th 17 cells. Because of its essential role in controlling differentiation and function of Th 17 cells, RORγ represents a potential therapeutic target for autoimmune diseases. To discover novel RORγ antagonists, we started the structure-activity relationships （SAR）studies of compound 1, obtained from a high-throughput screening campaign. Compound 1 had moderate potency against RORγ, however, this compound had structural alerts and several drawbacks, such as poor microsomal stability in liver S 9 and CYP inhibition. To solve these challenges, we decided to optimize compound 1 by improving two drug-likeness metrics, ligand efficiency（LE）and fraction of sp³ carbon atoms（Fsp³）. The X-ray co-crystal structure, utilized for our structure optimization, showed a unique U-shaped bioactive conformation. The efforts to stabilize the unique conformation through conformational constraint led to the identification of a novel RORγ antagonist 41 which had high potency against RORγ and significantly improved metabolic stability as well as reduced CYP inhibition. The HCl salt of compound 41 was orally effective in mice.

ACS（American Chemical Society National Meeting and Exposition）was held in San Francisco, America, between April 2 and 6, 2017. This 253^rd science meeting is a large-scale international academic meeting in the field of the various chemistries, and an audience is from all the countries. The symposium topics included “New reactions & Methodology”, “Total Synthesis of Complex Molecules”, “ACS Award for Creative Work in Synthetic Organic Chemistry”, “Macrocycles & Cyclopeptides in Medicinal Chemistry”, “Kinase Inhibitors for Immuno-inflammatory Diseases”, “MEDI Awards Symposium”, and so on. In this report, some impressive lectures about the new reaction developments from organic chemistry sessions and kinase inhibitors from medicinal chemistry sessions will be introduced.