Design, Synthesis, and Antifibrosis Activity in Liver of Nonsecosteroidal Vitamin D Receptor Agonists with Phenyl-pyrrolyl Pentane Skeleton

Liver fibrosis is characterized by
excessive deposition of extracellular
matrix (ECM) components and results in impaired liver function. Vitamin
D plays a critical role in the development of liver fibrosis as it
inhibits transforming growth factor β1 (TGFβ1)-induced
excessive deposition of ECM in activated hepatic stellate cells (HSCs).
Here, a series of novel nonsecosteroidal vitamin D receptor (VDR)
agonists with phenyl-pyrrolyl pentane skeleton was designed and synthesized.
Among them, seven compounds including 15a exhibited more
efficient inhibitory activity in collagen deposition and fibrotic
gene expression. Histological examination results displayed that compound 15a treatment prevented the development of hepatic fibrosis
that induced by carbon tetrachloride (CCl4) injections
in mice. In addition, compound 15a, unlike the positive
control calcipotriol and 1,25­(OH)2D3, did not
cause hypercalcemia that is toxic to nerve, heart, and many other
organs. These findings provide novel insights into drug discoveries
for hepatic fibrosis using nonsecosteroidal VDR modulators.