Design and Synthesis of Potent Inhibitor of Apoptosis (IAP) Proteins Antagonists Bearing an Octahydropyrrolo[1,2-a]pyrazine Scaffold as a Novel Proline Mimetic

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• 作者：Kentaro Hashimoto ; Bunnai Saito ; Naoki Miyamoto ; Yuya Oguro ; Daisuke Tomita ; Zenyu Shiokawa ; Moriteru Asano ; Hiroyuki Kakei ; Naohiro Taya ; Masanori Kawasaki ; Hiroyuki Sumi ; Masato Yabuki ; Kenichi Iwai ; Sei Yoshida ; Mie Yoshimatsu ; Kazunobu Aoyama ; Yohei Kosugi ; Takashi Kojima ; Nao Morishita ; Douglas R. Dougan ; Gyorgy P. Snell ; Shinichi Imamura ; Tomoyasu Ishikawa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1228-1246
• 全文大小：835K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound <b>45b>, which showed potent cellular IAP1 (cIAP1 ICb>50b>: 1.3 nM) and XIAP (ICb>50b>: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GIb>50b>: 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound <b>45b> bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound <b>45b> over XIAP. Because of its potent IAP inhibitory activities, compound <b>45b> (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: 鈭?3% at 30 mg/kg).