Design, synthesis and X-ray crystallographic study of new nonsecosteroidal vitamin D receptor ligands

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 20; pp. 6104 - 6107
• Main Authors: Demizu, Yosuke, Takahashi, Takeo, Kaneko, Fumiya, Sato, Yukiko, Okuda, Haruhiro, Ochiai, Eiji, Horie, Kyohei, Takagi, Ken-ichiro, Kakuda, Shinji, Takimoto-Kamimura, Midori, Kurihara, Masaaki
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.10.2011; Elsevier
• Subjects: amino acids; Animals; Biological and medical sciences; crystal structure; Crystallography, X-Ray; Drug Design; Ligands; Medical sciences; Miscellaneous; Models, Molecular; Nonsecosteroidal ligand; Pharmacology. Drug treatments; Protein Binding; Rats; Receptors, Calcitriol - chemistry; Receptors, Calcitriol - metabolism; transcription (genetics); vitamin D; Vitamin D receptor; X-ray crystallographic analysis; X-ray diffraction; X-ray crystallographic analysis; Vitamin D receptor; Nonsecosteroidal ligand; Nuclear receptor; Ligand; Alcohol; Branched compound; X ray diffraction; Biological activity; Hydroxyether; Vitamin D; Chemical synthesis; Non steroid compound; Hydrogen bond; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.08.047

We designed and synthesized nonsecosteroidal vitamin D receptor (VDR) ligands that formed H-bonds with six amino acid residues (Tyr143, Ser233, Arg270, Ser274, His301 and His393) of the VDR ligand-binding domain. The ligand YR335 exhibited potent transcriptional activity, which was comparable to those of 1α,25-dihydroxyvitamin D 3 and YR301. The crystal structure of the complex formed between YR335 and the VDR ligand-binding domain was solved, which revealed that YR335 formed H-bonds with the six amino acid residues mentioned above.