Systematic SAR study of the side chain of nonsecosteroidal vitamin D3 analogs

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 14; pp. 4495 - 4506
• Main Authors: Kashiwagi, Hirotaka, Ono, Yoshiyuki, Ohta, Masateru, Morikami, Kenji, Takahashi, Tadakatsu
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: 55% Rule; Alkenes - chemical synthesis; Alkenes - chemistry; Binding Sites; Biological and medical sciences; Calcitriol - analogs & derivatives; Calcitriol - chemical synthesis; carboxylic acids; Carboxylic Acids - chemistry; cholecalciferol; Computer Simulation; Hydrophobic and Hydrophilic Interactions; hydrophobicity; in vitro studies; Medical sciences; Nonsecosteroidal; Packing coefficient; Pentanoic Acids - chemical synthesis; Pentanoic Acids - chemistry; Pharmacology. Drug treatments; Protein Structure, Tertiary; receptors; Receptors, Calcitriol - agonists; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; VDR agonist; Vitamin D3; Vitamin D3; Nonsecosteroidal; 55% Rule; Packing coefficient; VDR agonist; Steroid; Agonist; Nuclear receptor; Side chain; Vitamin D; Structure activity relation; Non steroid compound; Colecalciferol; Biological receptor; Hormonal receptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.05.023

A series of nonsecosteroidal vitamin D3 analogs with carboxylic acid were explored. Through our systematic SAR studies on the side chain moiety, compound 6b was identified as the optimal compound showing excellent vitamin D receptor (VDR) agonistic activity. Compound 6b had the diethyl group in the terminal which was bound by (E)-olefin linker to the bisphenyl core. Calculating the volume of the side chain showed that the diethyl group in 6b filled the hydrophobic region of VDR with the ideal packing coefficient based on the 55% rule, and that this resulted in the most potent in vitro activity.