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.
abstract: 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 IC(50): 1.3 nM) and XIAP (IC(50): 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 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).
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Bunnai
authors.initials: B
authors.lastname: Saito
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tomita
authors.forename: Zenyu
authors.initials: Z
authors.lastname: Shiokawa
authors.forename: Moriteru
authors.initials: M
authors.lastname: Asano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kakei
authors.forename: Naohiro
authors.initials: N
authors.lastname: Taya
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sumi
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iwai
authors.forename: Sei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Mie
authors.initials: M
authors.lastname: Yoshimatsu
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Aoyama
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kosugi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.forename: Nao
authors.initials: N
authors.lastname: Morishita
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.forename: Gyorgy P
authors.initials: GP
authors.lastname: Snell
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057786:Peptidomimetics; D011392:Proline / Q000737:chemistry*
chemical_list: C579816:2-(2-(4,4-difluorocyclohexyl)-2-((N-methylalanyl)amino)acetyl)-N-(3,4-dihydro-2H-chromen-4-yl)-7-ethoxyoctahydropyrrolo(1,2-a)pyrazine-3-carboxamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D057786:Peptidomimetics; D011392:Proline