What Does It Take to Develop Structurally Complex Molecules by Total Synthesis? Rapid Process Development and GMP Manufacturing of E7130 Drug Substance for First-in-Human Clinical Study

• DOI: 10.1021/acs.oprd.4c00016
• Publication Date: 2024-04-15T11:14:36Z
• Authors: Takeo Sasaki; Kenzo Yahata; Minetaka Isomura; Isao Ohashi; Takashi Fukuyama; Yusuke Miyashita; Yuzo Watanabe; Norio Murai; Masaaki Matsuda; Atsushi Kamada; Yosuke Kaburagi; Kazunobu Kira; Kentaro Iso; Yuki Sato; Fumiyoshi Matsuura; Yasunobu Matsumoto; Hiroshi Azuma; Daisuke Iida; Tasuku Ishida; Wataru Itano; Satoshi Nagao; Masashi Seki; Akihiko Yamamoto; Yuji Yamamoto; Naoki Yoneda; Masayuki Matsukura; Osamu Asano; Akio Kayano; Katsuya Tagami; Takashi Owa; Yoshito Kishi
• Keywords: Drug Development

Process development of E7130 Drug Substance, which is a novel anticancer drug candidate, described. To accomplish rapid delivery such large and structurally complex substance for first-in-human (FIH) clinical trial, close collaboration among medicinal chemistry, process academia teams was required. The successful establishment suitable synthetic route in concise time frame while negotiating challenging chemical reactions (e.g., asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) reaction Zr/Ni-mediated ketone coupling reaction) described herein. Experience with the eribulin mesylate helpful anticipating overcoming logistical challenges encountered project. Based on this background, more than 10 g Substance has been successfully manufactured under Good Manufacturing Practice (GMP) controls within 1.5 years after chemistry team succeeded first total synthesis.