Design and synthesis of a monocyclic derivative as a selective ACC1 inhibitor by chemical modification of biphenyl ACC1/2 dual inhibitors. (1st April 2021)

• Record Type: Journal Article
• Authors: Mizojiri, Ryo; Tomita, Daisuke; Sasaki, Masako; Satoh, Yoshihiko; Yamamoto, Yukiko; Sumi, Hiroyuki; Maezaki, Hironobu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 35(2021)
• Publication Date: 2021-04-01
• Subjects: Acetyl-CoA carboxylase (ACC) 1 inhibitor -- Selectivity -- 14C acetate uptake inhibition -- Bioavailability -- Malonyl-CoA; ATP adenosine triphosphate -- BSA bovine serum albumin -- DBU 1, 8-diazabicyclo[5.4.0]undec-7-ene -- DIAD diisopropyl azodicarboxylate -- IPE diisopropyl ether -- DMF N, N-dimethylformamide -- DMSO dimethylsulfoxide -- DPPA diphenylphosphoryl azide -- EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HOBt 1-hydroxybenzotriazole -- MsCl methanesulfonyl chloride -- PBS phosphate buffered saline -- THF tetrahydrofuran; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116056
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A structure–activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of the linker in biaryl derivative 1 g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover novel phenoxybenzyloxy derivative 1i as a potent ACC1-selective inhibitor. Further chemical modification of this scaffold to improve cellular potency as well as physicochemical and pharmacokinetic (PK) properties produced N -2-(pyridin-2-ylethyl)acetamide derivative 1n, which showed highly potent ACC1-selective inhibition as well as sufficient PK profile for further in vivo evaluations. Oral administration of 1n significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of 100 mg/kg. Accordingly, our novel series of potent ACC1-selective inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid-related diseases.