22-Alkyl-20-epi-1alpha,25-dihydroxyvitamin D3 compounds of superagonistic activity: syntheses, biological activities and interaction with the receptor.

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Yamamoto K, Inaba Y, Yoshimoto N, Choi M, DeLuca HF, Yamada S

22-Alkyl-20-epi-1alpha,25-dihydroxyvitamin D3 compounds of superagonistic activity: syntheses, biological activities and interaction with the receptor.

J Med Chem. 2007 Mar 8;50(5):932-9. Epub 2007 Feb 14.

PubMed ID

17298045 [ View in PubMed

]

Abstract

We previously reported that 22R-methyl-20-epi-1,25-(OH)2D3 (3) possesses strong binding affinity for the vitamin D receptor (VDR) and shows superagonistic biological activities. To examine the effect of the length of an alkyl substituent at C(22) and to extend our compound library, we successfully synthesized 22R-ethyl-20-epi-1,25-(OH)2D3 (4) and 22R-butyl-20-epi-1,25-(OH)2D3 (5). Surprisingly, 22-ethyl analogue 4 showed stronger VDR binding affinity and transactivation potency than the superagonist of methyl analogue 3, but its calcemic activity in vivo was weaker than that of both the methyl analogue 3 and the natural hormone (1), while 22-butyl analogue 5 showed activities comparable to those of the hormone (1). A study of the docking of these new analogues to the VDR-LBD and alanine scanning mutational analysis demonstrated that 22-methyl and 22-ethyl substituents enhance the favorable hydrophobic interactions with residues lining the ligand binding pocket of the VDR, and that 22-butyl analogue 5 binds to the VDR by an induced fit mechanism.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Calcitriol	Vitamin D3 receptor	EC 50 (nM)	0.5	N/A	N/A	Details