Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors.

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. Kamata_Makoto@takeda.co.jp

Bioorganic & medicinal chemistry letters 2012 Jul 15

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Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Citation

Makoto Kamata, Tohru Yamashita, Asato Kina, Michiko Tawada, Satoshi Endo, Atsushi Mizukami, Masako Sasaki, Akiyoshi Tani, Yoshihide Nakano, Yuuki Watanabe, Naoki Furuyama, Miyuki Funami, Nobuyuki Amano, Kohji Fukatsu. Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors. Bioorganic & medicinal chemistry letters. 2012 Jul 15;22(14):4769-72