Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists

Moriteru Asano; Kentaro Hashimoto; Bunnai Saito; Zenyu Shiokawa; Hiroyuki Sumi; Masato Yabuki; Mie Yoshimatsu; Kazunobu Aoyama; Teruki Hamada; Nao Morishita; Douglas R Dougan; Clifford D Mol; Sei Yoshida; Tomoyasu Ishikawa

doi:10.1016/j.bmc.2013.07.020

Design, stereoselective synthesis, and biological evaluation of novel tri-cyclic compounds as inhibitor of apoptosis proteins (IAP) antagonists

Bioorg Med Chem. 2013 Sep 15;21(18):5725-37. doi: 10.1016/j.bmc.2013.07.020. Epub 2013 Jul 18.

Authors

Moriteru Asano¹, Kentaro Hashimoto, Bunnai Saito, Zenyu Shiokawa, Hiroyuki Sumi, Masato Yabuki, Mie Yoshimatsu, Kazunobu Aoyama, Teruki Hamada, Nao Morishita, Douglas R Dougan, Clifford D Mol, Sei Yoshida, Tomoyasu Ishikawa

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. [email protected]

PMID: 23928071
DOI: 10.1016/j.bmc.2013.07.020

Abstract

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.

Keywords: Inhibitor of apoptosis proteins (IAP); Octahydro-1H-cyclopropa[4,5]pyrrolo[1,2-a]pyrazine; Simmons−Smith cyclopropanation.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Benzopyrans / chemical synthesis
Benzopyrans / pharmacokinetics
Benzopyrans / therapeutic use
Binding Sites
Breast Neoplasms / drug therapy
Cell Line, Tumor
Crystallography, X-Ray
Drug Design*
Female
Half-Life
Humans
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
Inhibitor of Apoptosis Proteins / metabolism
Mice
Molecular Dynamics Simulation
Protein Structure, Tertiary
Pyrazines / chemical synthesis
Pyrazines / chemistry*
Pyrazines / pharmacokinetics
Pyrazines / therapeutic use
Pyrroles / chemical synthesis*
Pyrroles / chemistry
Pyrroles / pharmacokinetics
Pyrroles / therapeutic use
RNA, Messenger / metabolism
Stereoisomerism
Transplantation, Heterologous
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / metabolism

Substances

(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
Benzopyrans
Inhibitor of Apoptosis Proteins
Pyrazines
Pyrroles
RNA, Messenger
Tumor Necrosis Factor-alpha
octahydropyrrolo(1,2-a)pyrazine