Structural requirements of cholenamide derivatives as the LXR ligands

Kana Saida-Tamiya; Minoru Tamiya; Genki Sekiya; Kazunori Isobe; Takaaki Kitazawa; Nobuhisa Isaka; Ayako Matsukawa; Kohichi Kawahara; Akihiko Komuro; Masaji Ishiguro

doi:10.1016/j.bmcl.2019.03.051

Structural requirements of cholenamide derivatives as the LXR ligands

Bioorg Med Chem Lett. 2019 Jun 1;29(11):1330-1335. doi: 10.1016/j.bmcl.2019.03.051. Epub 2019 Mar 30.

Affiliations

¹ Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan.
² Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan. Electronic address: tamiya@nupals.ac.jp.
³ Department of Biochemistry, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan.
⁴ Department of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata 956-8603, Japan. Electronic address: ishiguro@nupals.ac.jp.

PMID: 30952591
DOI: 10.1016/j.bmcl.2019.03.051

Abstract

A study of the structural requirements of cholic acid derivatives as liver X receptor (LXR) ligands was performed. A model of cholenamide derivative 1 complexed with LXR showed that the C24 carbonyl oxygen forms a hydrogen bond with His435 located close to Trp457. The N,N-dimethyl group is located in a hydrophobic pocket. Based on these data, we designed compounds with high affinity for LXRs. Cholenamide derivatives 1-11 were synthesized from 3β-acetyl-Δ⁵-cholenic acid 20, and lactams 12-19 were synthesized from alcohol 25. Tertiary amides 3 and 4 showed higher activity in reporter assays, and compounds with hydrophobic residues exhibited the highest activity of all derivatives. The stereochemistry at C23 was found to be an important determinant of EC₅₀ and gene transactivation, as each isomer exhibited different activity.

Keywords: 24,25-Epoxycholesterol; Cholic acid; LXR; Molecular modeling; N, N-Dimethylcholenamide.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Animals
Cholic Acid / chemical synthesis
Cholic Acid / chemistry
Cholic Acid / pharmacology*
Dose-Response Relationship, Drug
Humans
Ligands
Liver X Receptors / metabolism*
Mice
Molecular Structure
Structure-Activity Relationship

Substances

Amides
Ligands
Liver X Receptors
Cholic Acid