C22- to C26,27-Fluoro-2-(3-hydroxypropyl)-19-norvitamin D3, Side-chain Fluorinated MART-10s Suppress IL-19 Secretion from Th17-stimulated Keratinocytes: Potent Therapeutic Effects on Psoriasis Models

Abstract Psoriasis is a chronic inflammatory disorder characterized by skin inflammation and hyperproliferation due to abnormal differentiation of basal keratinocytes. The etiology is unclear, but psoriasis has been described as a prototypic Th17-mediated disease. Interleukin-19 (IL-19) is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis, and IL-19 production is induced in keratinocytes by IL-17A. However, the therapeutic applications of IL-19 for human disease have yet to be developed. We synthesized 24 new kinds of side-chain fluorinated 2-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 analogues based on the MART-10 and MART-11 skeletons, and their suppressive effects on keratinocyte IL-19 secretion were assessed. Surprisingly, more than half of the analogues exhibited potent suppressive effects with much greater efficiency than calcipotriol, a commonly clinically used medicine for the treatment of psoriasis. Furthermore, one of the best analogues, 24F2-MART-10, was selected to study therapeutic effects on psoriasis model mice. We found that comparable efficacy was achieved using only one-fifth of the volume of calcipotriol, highlighting the superior therapeutic potency of 24F2-MART-10. Osteocalcin promoter transactivation activity of all 24 analogues was also tested.