Design, synthesis, and structure–activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors

Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene po...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (11), p.3643-3647
Hauptverfasser:	Kamata, Makoto, Yamashita, Tohru, Kina, Asato, Funata, Masaaki, Mizukami, Atsushi, Sasaki, Masako, Tani, Akiyoshi, Funami, Miyuki, Amano, Nobuyuki, Fukatsu, Kohji
Format:	Artikel
Sprache:	eng
Schlagworte:	ACC Acetyl-CoA carboxylase Acetyl-CoA Carboxylase - antagonists & inhibitors Acetyl-CoA Carboxylase - metabolism Animals Biological and medical sciences Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Humans Lactones - chemistry Lipophilicity Liver - metabolism Medical sciences Metabolic stability microsomes pharmacokinetics Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacokinetics pyridines Rats risk factors Spiro Compounds - chemistry Spiro-piperidine Stereoisomerism Structure-Activity Relationship structure-activity relationships
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Zusammenfassung:	Spiro-lactone (S)-1 is a potent acetyl-CoA carboxylase (ACC) inhibitor and was found to be metabolically liable in human hepatic microsomes. To remove one of the risk factors in human study by improving the metabolic stability, we focused on modifying the spiro-lactone ring and the benzothiophene portion of the molecule. Spiro-imide derivative 8c containing a 6-methylthieno[2,3-b]pyridine core exhibited potent ACC inhibitory activity and favorable pharmacokinetic profiles in rats.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.04.047