title: 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.
abstract: 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]: IC50 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: zenyu.shiokawa@takeda.com.
authors.forename: Zenyu
authors.initials: Z
authors.lastname: Shiokawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Bunnai
authors.initials: B
authors.lastname: Saito
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sumi
authors.forename: Masato
authors.initials: M
authors.lastname: Yabuki
authors.forename: Mie
authors.initials: M
authors.lastname: Yoshimatsu
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kosugi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Debori
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: Sei
authors.initials: S
authors.lastname: Yoshida
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D011719:Pyrazines
keywords: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; 1-hydroxybenzotriazole; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; Ac; CDCl(3); DIPEA; DMF; DMSO; DMT-MM; EDC; Et; HATU; HOBT; Hexahydropyrazino[1,2-a]indole; Inhibitors of apoptosis proteins; Me; N,N-dimethylformamide; N-ethyldiisopropylamine; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; Pd(OH)(2)/C; Pd/C; Pr; Quant.; TFA; THF; XIAP; acetyl; cIAP; deuteratedchloroform; dimethyl sulfoxide; ethyl; i; iso; melting point; methyl; mp; palladium hydroxide on carbon; palladium on carbon; propyl; quantitative yield; satd; saturated aqueous; tert; tertiary; tetrahydrofuran; trifluoroacetic acid