| Autor: |
Haginoya N; Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, 134-8630 Tokyo, Japan., Suzuki M; R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, 140-8710 Tokyo, Japan., Suzuki M; Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, 134-8630 Tokyo, Japan., Ishigai Y; R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, 140-8710 Tokyo, Japan., Terayama K; Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, 134-8630 Tokyo, Japan., Kanda A; Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, 134-8630 Tokyo, Japan., Sugita K; R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, 140-8710 Tokyo, Japan. |
| Abstrakt: |
Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A -( 1 S , 3 R )- 14i , showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors. |
