1266228-99-2Relevant academic research and scientific papers
Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic
Hashimoto, Kentaro,Saito, Bunnai,Miyamoto, Naoki,Oguro, Yuya,Tomita, Daisuke,Shiokawa, Zenyu,Asano, Moriteru,Kakei, Hiroyuki,Taya, Naohiro,Kawasaki, Masanori,Sumi, Hiroyuki,Yabuki, Masato,Iwai, Kenichi,Yoshida, Sei,Yoshimatsu, Mie,Aoyama, Kazunobu,Kosugi, Yohei,Kojima, Takashi,Morishita, Nao,Dougan, Douglas R.,Snell, Gyorgy P.,Imamura, Shinichi,Ishikawa, Tomoyasu
, p. 1228 - 1246 (2013/03/28)
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: -53% at 30 mg/kg).
Design, synthesis, and biological activities of novel hexahydropyrazino[1, 2-a]indole derivatives as potent inhibitors of apoptosis (IAP) proteins antagonists with improved membrane permeability across MDR1 expressing cells
Shiokawa, Zenyu,Hashimoto, Kentaro,Saito, Bunnai,Oguro, Yuya,Sumi, Hiroyuki,Yabuki, Masato,Yoshimatsu, Mie,Kosugi, Yohei,Debori, Yasuyuki,Morishita, Nao,Dougan, Douglas R.,Snell, Gyorgy P.,Yoshida, Sei,Ishikawa, Tomoyasu
, p. 7938 - 7954 (2014/01/06)
We previously reported octahydropyrrolo[1,2-a]pyrazine derivative 2 (T-3256336) as a potent antagonist for inhibitors of apoptosis (IAP) proteins. Because compound 2 was susceptible to MDR1 mediated efflux, we developed another scaffold, hexahydropyrazino[1,2-a]indole, using structure-based drug design. The fused benzene ring of this scaffold was aimed at increasing the lipophilicity and decreasing the basicity of the scaffold to improve the membrane permeability across MDR1 expressing cells. We established a chiral pool synthetic route to yield the desired tricyclic chiral isomers. Chemical modification of the core scaffold led to a representative compound 50, which showed strong inhibition of IAP binding (X chromosome-linked IAP [XIAP]: IC 50 23 nM and cellular IAP [cIAP]: IC50 1.1 nM) and cell growth inhibition (MDA-MB-231 cells: GI50 2.8 nM) with high permeability and low potential of MDR1 substrate.
Heterocyclic Compound
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Page/Page column 66, (2011/02/26)
The present invention provides a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof. The compound of the present invention shows a strong IAP antagonistic activity.
