Design, synthesis and evaluation of side-chain hydroxylated derivatives of lithocholic acid as potent agonists of the vitamin D receptor (VDR)

Carmen M González (1) , Sunil Gaikwad (1) , Gonzalo Lasanta (1) , Julian Loureiro (1) , Niclas Nilsson (2) , Carole Peluso-Iltis (3) , Natacha Rochel (3) , Antonio Mouriño (1)

1 USC - Universidade de Santiago de Compostela [Spain]
2 LEO Pharma [Bellerup, Denmark]
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

A high number of biologically active and low-calcemic secosteroidal ligands of the vitamin D receptor (VDR) have been developed, some of which are already used clinically although with limited success in the treatment of hyperproliferative diseases because the required pharmaceutical dosages induce toxicity. We describe here the in silico design, synthesis, structural analysis and biological evaluation of two novel active lithocholic acid derivatives hydroxylated at the side chain as highly potent inhibitors of atopic dermatitis-relevant keratinocyte inflammation of potential therapeutic interest.

Mots clés: Transcription; Vitamin D receptor; VDR agonist; Lithocholic acid derivatives; In silico design; Stereoselective synthesis; Structure-function

Domaines: Chimie thérapeutique; Biologie structurale [q-bio.BM]

Carmen M González, Sunil Gaikwad, Gonzalo Lasanta, Julian Loureiro, Niclas Nilsson, et al.. Design, synthesis and evaluation of side-chain hydroxylated derivatives of lithocholic acid as potent agonists of the vitamin D receptor (VDR). Bioorganic Chemistry, 2021, 115, pp.105202. ⟨10.1016/j.bioorg.2021.105202⟩. ⟨hal-03861099⟩