title: Design, synthesis, and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, Fujisawa, Kanagawa, Japan. Kamata_Makoto@takeda.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamata
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Asato
authors.initials: A
authors.lastname: Kina
authors.forename: Masaaki
authors.initials: M
authors.lastname: Funata
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizukami
authors.forename: Masako
authors.initials: M
authors.lastname: Sasaki
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Tani
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukatsu
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D007783:Lactones / Q000737:chemistry*; D008099:Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D010880:Piperidines; D013141:Spiro Compounds; D000103:Acetyl-CoA Carboxylase