Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists.
We recently reported the discovery of octahydropyrrolo[1,2-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-cyclopropa[4,5]pyrrolo[1,2-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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. moriteru.asano@takeda.com
Moriteru
M
Asano
Kentaro
K
Hashimoto
Bunnai
B
Saito
Zenyu
Z
Shiokawa
Hiroyuki
H
Sumi
Masato
M
Yabuki
Mie
M
Yoshimatsu
Kazunobu
K
Aoyama
Teruki
T
Hamada
Nao
N
Morishita
Douglas R
DR
Dougan
Clifford D
CD
Mol
Sei
S
Yoshida
Tomoyasu
T
Ishikawa
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006207:Half-Life; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013237:Stereoisomerism; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
C587127:(1aS,4S,6aR,7aS)-5-((2S)-2-cyclohexyl-2-((N-methyl-l-alanyl)amino)acetyl)-N-((4R)-3,4-dihydro-2H-chromen-4-yl)octahydro-1H-cyclopropa(4,5)pyrrolo(1,2-a)pyrazine-4-carboxamide dihydrochloride; D001578:Benzopyrans; D051034:Inhibitor of Apoptosis Proteins; D011719:Pyrazines; D011758:Pyrroles; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C587126:octahydropyrrolo(1,2-a)pyrazine
Inhibitor of apoptosis proteins (IAP); Octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine; Simmons−Smith cyclopropanation