The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action

Yuki Kitao; Tadataka Saito; Satoshi Watanabe; Yasuhiro Ohe; Koichi Takahashi; Tatsuo Akaki; Tsuyoshi Adachi; Satoki Doi; Kenji Yamanaka; Yasutaka Murai; Makoto Oba; Takayoshi Suzuki

doi:10.1016/j.bmcl.2022.129110

The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action

Bioorg Med Chem Lett. 2023 Jan 15:80:129110. doi: 10.1016/j.bmcl.2022.129110. Epub 2022 Dec 20.

Authors

Affiliations

¹ Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan; Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan. Electronic address: yuki.kitao@jt.com.
² Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
³ Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc, 1-1, Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
⁴ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan.
⁵ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan; The Institute of Scientific and Industrial Research Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.

PMID: 36563792
DOI: 10.1016/j.bmcl.2022.129110

Abstract

AMP deaminase 2 (AMPD2) has been thought to play an important role in energy homeostasis and immuno-oncology, while selective AMPD2 inhibitors are highly demanded to clarify the physiological function of AMPD2. In this report, we describe selective AMPD2 inhibitors inducing allosteric modulation. Based on hypothesis that compounds that exhibit increased inhibition by preincubation would cause conformational change of the enzyme, starting from HTS hit compound 4, we discovered compound 8 through the SAR study. From X-ray structural information of 8, this chemical series has a novel mechanism of action that changes the substrate pocket to prevent AMP from binding. Further elaboration of compound 8 led to the tool compound 21 which exhibited potent inhibitory activity of AMPD2 in ex vivo evaluation of mouse liver.

Keywords: AMPD2 inhibitor; Allosteric modulation; Conformational change.

MeSH terms

AMP Deaminase* / metabolism
Animals
Mice

Substances

AMP Deaminase