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

  • Bioorg Med Chem Lett. 2012 Jan 15;22(2):1136-41. doi: 10.1016/j.bmcl.2011.11.100.
Atsushi Suda  1 ,  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
Affiliations
  • 1. Kamakura Laboratories, Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. [email protected]
PMID: 22192591 DOI: 10.1016/j.bmcl.2011.11.100
Abstract

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 Hsp90α (K(d)=0.52nM) and strong anti-proliferative activity against human Cancer cell lines (HCT116 IC(50)=0.15μM, NCI-N87 IC(50)=0.066μM). 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%).

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