MEDCHEM NEWS
Online ISSN : 2432-8626
Print ISSN : 2432-8618
ISSN-L : 2432-8618
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Volume 33, Issue 3
Displaying 1-18 of 18 articles from this issue
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  • Challenges of Kyowa Kirin to successive creation of Life-changing value
    Yoshifumi Torii
    2023 Volume 33 Issue 3 Pages 106-111
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_106
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    Kyowa Kirin Co., Ltd. which has been established through the merger of Kyowa Hakko Kogyo and Kirin Pharma, is targeting to become a Japan-based global specialty pharma and continues to challenge to the successive creation of life-changing value. Our R&D Division is committed to advancing “Technology-driven Drug Discovery” making the most of open innovation, while leveraging its strengths in disease-oriented intelligence and technology-oriented research infrastructure, which is the Kyowa Kirin’s R&D Concept. In the area of small molecule drug discovery, we are also working to establish an innovative drug discovery technology platform by integrating excellent external technologies with its own strengths. In this report, our challenges in drug discovery research where we are striving to “create life-changing value with clear competitive advantages” will be described.
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DISCOVERY
  • Discovery and Optimization of Potent NAMPT Activators for the Treatment of Obesity
    Mayuko Akiu, Takashi Tsuji, Kouki Iida
    2023 Volume 33 Issue 3 Pages 112-116
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_112
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    Boosting NAD+, which plays a pivotal role in energy metabolism, has positive effects on metabolic regulation. Therefore, activation of NAMPT is an attractive therapeutic approach for the treatment of metabolic disorders. We conducted a drug discovery research on NAMPT activators aiming a novel therapeutic agent for obesity. Intensive derivatization starting from HTS hits culminated in the discovery of DS68702229 as a potent, novel NAMPT activator with an excellent PK profile. Oral administration of DS68702229 to DIO mice led to elevation of NAD+ levels in various tissues, along with significant and continuous decrease in body weight. Since DS68702229 was Ames-positive, an SAR study was undertaken in order to mitigate the mutagenic risk. Ultimately, compound 11 was obtained as a potent, Ames-negative NAMPT activator with a good ADME profile.
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  • Discovery of tetracyclic TRK-selective inhibitor CH7057288
    Toshiya Ito
    2023 Volume 33 Issue 3 Pages 117-121
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_117
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    Kinase fusions involving tropomyosin receptor kinases (TRKs) have been proven to act as strong oncogenic drivers and are therefore recognized as attractive therapeutic targets. We screened an in-house kinase-focused library and identified a promising hit compound with a unique tetracyclic scaffold. Compound 1 showed high TRK selectivity but moderate cell growth inhibitory activity as well as a potential risk of inducing CYP3A4. Chemical modification intended to improve TRK inhibition and avoid CYP3A4 induction enabled us to identify an orally bioavailable, selective, and potent TRK inhibitor CH7057288. The details of design, synthesis, and biological activities of the tetracyclic derivatives will be presented.
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  • Discovery of MT-7117（dersimelagon phosphoric acid）as a novel MC1R Agonist
    Atsushi Sato, Yasuo Yamamoto, Kenji Morokuma, Masahiko Miyashiro, Tsuy ...
    2023 Volume 33 Issue 3 Pages 122-126
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_122
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    Melanocortin 1 receptor (MC1R) agonists are expected as promising therapeutic agents for skin diseases and autoimmune diseases by promoting melanogenesis, inhibiting inflammation and fibrosis. Although α-melanocyte-stimulating hormone (α-MSH) analog afamelanotide is approved for the treatment of erythropoietic protoporphyria (EPP) , it is used as a subcutaneous implant formulation, and the development of a more convenient oral drug is desired. In the course of our exploration, we successfully discovered MT-7117 (dersimelagon phosphoric acid) with potent MC1R agonistic activity, excellent pharmacokinetic, and safety profiles by “introduction of carboxylic acid”, “introduction of fluorine atom” and “conversion to tertiary amide compound”.
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  • Fragment-based discovery of a novel, brain penetrant, orally active HDAC2 inhibitor
    Taichi Tamai, Shunpei Ishikawa, Shin Miyamura, Emiliano Tamanini, Domi ...
    2023 Volume 33 Issue 3 Pages 127-131
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_127
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    Histone deacetylase (HDAC) enzymes play a key role in post-translational modifications which makes them important therapeutic targets for a number of indications including neurodegeneration. HDAC2 was found to be responsible for the reduction of histone acetylation resulting in decreased expression of key genes associated with learning and memory. These findings suggest that targeting this class of epigenetic targets, in particular the development of a brain penetrant HDAC2 inhibitor, could be beneficial for the treatment of neurodegenerative diseases. We successfully applied our fragment-based drug discovery (FBDD) platform to identify a novel, potent and brain penetrant HDAC2 inhibitor. Structure-based drug design (SBDD) guided by the numerous protein-ligand complex crystal structures allowed us to significantly improve the binding affinity of the initial fragment hit while maintaining ideal physicochemical properties for CNS indications. The resulting lead compound is capable of significantly increase histone H4K12 acetylation levels in vitro and in vivo.
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DISCOVERY
  • Gram-Scale Synthesis of Anticancer Drug Candidate E7130 to Supply Clinical Trials
    Isao Ohashi, Yoshito Kishi
    2023 Volume 33 Issue 3 Pages 132-135
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_132
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    Halichondrins are marine polyether macrolides with complex and unique structures. Despite their promising in vivo anti-cancer efficacy, the limited supply from the natural sources has prevented drug development with intact halichondrins. Alternatively, recent studies have shown that total synthesis of halichondrins could solve the problem of limited material supply. This has encouraged drug discovery/development efforts using intact halichondrins and has led to the identification of E7130 as a promising anti-cancer drug candidate through total synthesis. Through close collaboration, timely information sharing, and intensive process research between Harvard University and Eisai, GMP manufacturing of E7130 was achieved on multi-gram scale in about 1.5 years from its total synthesis on a milligram scale in the early stages of drug discovery. In this manufacturing, 11.5g of highly pure (99.8%) E7130 drug substance was successfully synthesized without any HPLC purification, which was used in a Phase 1 clinical trial.
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SEMINAR
  • Development of molecular-targeted chemogenetics for understanding higher brain functions
    Shigeki Kiyonaka, Tomohiro Doura
    2023 Volume 33 Issue 3 Pages 136-141
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_136
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    Higher brain functions such as memory and learning are produced by neural circuit composed of complex interaction between numerous neurons and glia cells in the brain. To understand higher brain functions, cell manipulation techniques such as optogenetics and chemogenetics are developed, which allow cell-type-specific control in the neural circuit in vivo. However, given that cellular signals are evoked by artificially-designed receptors in these methods, these may not reflect physiological responses. In this review, we describe a new direction of chemogenetics termed “molecular-targeted chemogenetics”, which will allow regulation of target endogenous receptors in a cell-type-specific manner in live animals.
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Coffee Break
REPORT
  • Report on 265th American Chemical Society National Meeting & Exposition
    Tomoya Miura
    2023 Volume 33 Issue 3 Pages 143-146
    Published: August 01, 2023
    Released on J-STAGE: August 01, 2023
    DOIhttps://doi.org/10.14894/medchem.33.3_143
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    The 265th ACS National Meeting & Exposition was held in Indianapolis, Indiana, USA, for five days from March 26, 2023. The theme of this meeting was “Crossroads of Chemistry”, and Prof. MacMillan, the Nobel Prize laureate in Chemistry 2021, was invited as a keynote speaker. This international conference is composed of a large number of specialized fields in chemistry, and I attended lectures related to drug discovery mainly in the Division of Medicinal Chemistry (MEDI) . This report highlights some interesting topics presented at MEDI and the Division of Computers in Chemistry (COMP) .
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