Design,stereoselective synthesis,and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists |
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Authors: | Moriteru Asano Kentaro Hashimoto Bunnai Saito Zenyu Shiokawa Hiroyuki Sumi Masato Yabuki Mie Yoshimatsu Kazunobu Aoyama Teruki Hamada Nao Morishita Douglas R Dougan Clifford D Mol Sei Yoshida Tomoyasu Ishikawa |
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Institution: | 1. Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan;2. Structural Biology, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA |
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Abstract: | We recently reported the discovery of octahydropyrrolo1,2-a]pyrazine A as a lead compound for an inhibitor of apoptosis proteins (IAP) antagonist. To develop IAP antagonists with favorable PK profiles, we designed novel tri-cyclic compounds, octahydro-1H-cyclopropa4,5]pyrrolo1,2-a]pyrazines 1 and 2 based on co-crystal structural analysis of A with cellular IAP-1 (cIAP-1). The additional cyclopropane moiety was used to block the predicted metabolic site of compound A without detriment to the binding affinity for cIAP. Compounds 1 and 2 were stereoselectively synthesized via intermediates 4a and 5b′, which were obtained by Simmons?Smith cyclopropanation of ethylester 3a and silyl ether 3b′. Compounds 1 and 2 showed strong growth inhibition in MDA-MB-231 breast cancer cells and improved metabolic stability in comparison to A. Compound 2 exhibited significant in vivo PD effects to increase tumor necrosis factor-alpha mRNA in a dose dependent manner. |
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Keywords: | Inhibitor of apoptosis proteins (IAP) Simmons?Smith cyclopropanation |
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