Design and synthesis of a monocyclic derivative as a selective ACC1 inhibitor by chemical modification of biphenyl ACC1/2 dual inhibitors

Ryo Mizojiri; Daisuke Tomita; Masako Sasaki; Yoshihiko Satoh; Yukiko Yamamoto; Hiroyuki Sumi; Hironobu Maezaki

doi:10.1016/j.bmc.2021.116056

Design and synthesis of a monocyclic derivative as a selective ACC1 inhibitor by chemical modification of biphenyl ACC1/2 dual inhibitors

Bioorg Med Chem. 2021 Apr 1:35:116056. doi: 10.1016/j.bmc.2021.116056. Epub 2021 Feb 14.

Authors

Ryo Mizojiri¹, Daisuke Tomita², Masako Sasaki², Yoshihiko Satoh², Yukiko Yamamoto², Hiroyuki Sumi², Hironobu Maezaki²

Affiliations

¹ Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: ryo.mizojiri@takeda.com.
² Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

PMID: 33607488
DOI: 10.1016/j.bmc.2021.116056

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.

Keywords: (14)C acetate uptake inhibition; Acetyl-CoA carboxylase (ACC) 1 inhibitor; Bioavailability; Malonyl-CoA; Selectivity.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry
Acetamides / pharmacology*
Acetyl-CoA Carboxylase / antagonists & inhibitors*
Acetyl-CoA Carboxylase / metabolism
Animals
Benzyl Compounds / chemical synthesis
Benzyl Compounds / chemistry
Benzyl Compounds / pharmacology*
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Structure-Activity Relationship

Substances

Acetamides
Benzyl Compounds
Enzyme Inhibitors
acetamide
ACACA protein, human
ACC1 protein, mouse
Acetyl-CoA Carboxylase