Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors

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• 作者：Atsushi Suda ; ^{sudaats@chugai-pharm.co.jp} ; Hiroshi Koyano ; Tadakatsu Hayase ; Kihito Hada ; Ken-ichi Kawasaki ; Susumu Komiyama ; Kiyoshi Hasegawa ; Takaaki A. Fukami ; Shigeo Sato ; Takaaki Miura ; Naomi Ono ; Toshikazu Yamazaki ; Ryoichi Saitoh ; Nobuo Shimma ; Yasuhiko Shiratori ; Takuo Tsukuda
• 关键词：Structure-based drug design ; Lead optimization ; Macrocyclic molecule ; Antitumor agent ; Hsp90 inhibitor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：15 January, 2012
• 年：2012
• 卷：22
• 期：2
• 页码：1136-1141
• 全文大小：718 K

文摘

Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90¦Á (K_d = 0.52 nM) and strong anti-proliferative activity against human cancer cell lines (HCT116 IC₅₀ = 0.15 ¦ÌM, NCI-N87 IC₅₀ = 0.066 ¦ÌM). CH5164840 displayed high oral bioavailability in mice (F = 70.8 % ) and potent antitumor efficacy in a HCT116 human colorectal cancer xenograft model (tumor growth inhibition = 83 % ).