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 45, which showed potent cellular IAP1 (cIAP1 IC₅₀: 1.3 nM) and XIAP (IC₅₀: 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI₅₀: 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: 鈭?3% at 30 mg/kg).