Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors.
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.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. Kamata_Makoto@takeda.co.jp
Makoto
M
Kamata
Tohru
T
Yamashita
Asato
A
Kina
Michiko
M
Tawada
Satoshi
S
Endo
Atsushi
A
Mizukami
Masako
M
Sasaki
Akiyoshi
A
Tani
Yoshihide
Y
Nakano
Yuuki
Y
Watanabe
Naoki
N
Furuyama
Miyuki
M
Funami
Nobuyuki
N
Amano
Kohji
K
Fukatsu
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013141:Spiro Compounds; C031280:pyrazole; D000103:Acetyl-CoA Carboxylase