| Autor: |
Mizojiri, Ryo, Asano, Moriteru, Tomita, Daisuke, Banno, Hiroshi, Nii, Noriyuki, Sasaki, Masako, Sumi, Hiroyuki, Satoh, Yoshihiko, Yamamoto, Yukiko, Moriya, Takeo, Satomi, Yoshinori, Maezaki, Hironobu |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
We initiated our structure–activity relationship (SAR) studies for selective ACC1 inhibitors from 1aas a lead compound. SAR studies of bicyclic scaffolds revealed many potent and selective ACC1 inhibitors represented by 1f; however most of them had physicochemical issues, particularly low aqueous solubility and potent CYP inhibition. To address these two issues and improve the druglikeness of this chemical series, we converted the bicyclic scaffold into a monocyclic framework. Ultimately, this lead us to discover a novel monocyclic derivative 1qas a selective ACC1 inhibitor, which showed highly potent and selective ACC1 inhibition as well as acceptable solubility and CYP inhibition profiles. Since compound 1qdisplayed favorable bioavailability in mouse cassette dosing testing, we conducted in vivo PD studies of this compound. Oral administration of 1qsignificantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of more than 30 mg/kg. Accordingly, our novel series of selective ACC1 inhibitors represents a set of useful orally available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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