Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic.

@article{Hashimoto2013DesignAS,
  title={Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic.},
  author={Kentaro Hashimoto and Bunnai Saito and Naoki Miyamoto and Yuya Oguro and Daisuke Tomita and Zenyu Shiokawa and Moriteru Asano and Hiroyuki Kakei and Naohiro Taya and Masanori Kawasaki and Hiroyuki Sumi and Masato Yabuki and Kenichi Iwai and Sei Yoshida and Mie Yoshimatsu and Kazunobu Aoyama and Yohei Kosugi and Takashi Kojima and Nao Morishita and Douglas R. Dougan and Gyorgy P Snell and Shinichi Imamura and Tomoyasu Ishikawa},
  journal={Journal of medicinal chemistry},
  year={2013},
  volume={56 3},
  pages={
          1228-46
        }
}
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… CONTINUE READING