Koki Yamamoto - Structure–Activity Relationships for Development of Neurokinin-3 Receptor Antagonists: Reducing Environmental Impact

Aims and Scope

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It is my great pleasure to introduce Dr. Koki Yamamotos thesis for Springer Theses. He joined our group at Kyoto University in April 2013 and started his scientific career under the supervision of Prof. Nobutaka Fujii, Prof. Hiroaki Ohno, and myself. During his six-year career at Kyoto University, he performed several structureactivity relationship studies of receptor ligands for neurokinin-3 receptor (NK3R), which regulates reproductive neuroendocrine systems.

His initial project as an undergraduate student focused on the development of novel NK3R antagonist peptides with resistance against proteolytic degradation. He learned a series of technical skills for medicinal chemistry, including solid-phase peptide synthesis and bioassays. In his doctoral studies at the Graduate School of Pharmaceutical Sciences, Kyoto University from 2014, he engaged in the development of selective NK3R antagonists with reduced environmental impact, which could be converted into substance(s) with much lower activity after excretion from the target animal(s). His unique concern was derived from research experience at the Animal Resource Science Center, Graduate School of Agricultural and Life Science, The University of Tokyo, in collaboration with Prof. Kei-ichiro Maeda (The University of Tokyo) and his colleagues in the snow season of 2014. He realized that large portions of bioactive agents were excreted from the target animal(s) and could be released into the natural environment without being metabolized or degraded. To minimize the effect of the bioactive ingredient(s) on non-target animals, he designed novel NK3R antagonists with decreased bioactivity under environmental conditions. During the course of his studies, he also investigated the synthesis of unprecedented heterocycles, which could be employed as scaffolds for novel NK3R antagonists. It should be noted that his scientific contributions included many collaborative works with Prof. Maeda, Prof. Hiroko Tsukamura (Nagoya University), Prof. Satoshi Ohkura (Nagoya University), and their colleagues, in which the in vivo bioactivities of several agents for reproductive functions were investigated.

This comprehensive thesis includes a design concept, chemistry, biological evaluations, and chemical properties, which will be informative for the development of novel NK3R antagonists and for the design of pharmaceutical agents with reduced environmental impact. He has published three articles related to this thesis in medicinal chemistry journals. I very much appreciate his continuous efforts to achieve the project goals.

The author would also like to express his sincere appreciation to Prof. Hiroaki Ohno, Prof. Nobutaka Fujii, Dr. Shinya Oishi, and Dr. Shinsuke Inuki (Kyoto University) for their kind guidance, helpful advice, and encouragement throughout this study.

The author is profoundly grateful to Dr. Akira Hirasawa, Dr. Toru Nakatsu (Kyoto University), Prof. Kei-ichiro Maeda, Dr. Fuko Matsuda (The University of Tokyo), Prof. Hiroko Tsukamura, Prof. Satoshi Ohkura (Nagoya University), and Dr. Masahito Ohue, Dr. Yasushi Yoshikawa (Tokyo Institute of Technology) for their professional guidance as well as technical supports to accomplish this research.