Systematic SAR study of the side chain of nonsecosteroidal vitamin D₃ analogs.
A series of nonsecosteroidal vitamin D(3) 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.
Research Division, Chugai Pharmaceutical Co. Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. kashiwagihrt@chugai-pharm.co.jp
Hirotaka
H
Kashiwagi
Yoshiyuki
Y
Ono
Masateru
M
Ohta
Kenji
K
Morikami
Tadakatsu
T
Takahashi
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D002264:Carboxylic Acids / Q000737:chemistry; D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000737:chemistry; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
C575892:(S)-5-(4-(1-ethyl-1-(4-((E)-3-ethyl-3-hydroxy-1-penteny1)-3-methylphenyl)-propyl)-2-methylphenoxy)-4-hydroxypentanoic acid; D000475:Alkenes; D002264:Carboxylic Acids; D010421:Pentanoic Acids; D018167:Receptors, Calcitriol; D002117:Calcitriol