title: A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Encephalomyelitis without Causing Hypercalcemia.
abstract: Vitamin D receptor (VDR) agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25-(OH)(2)D(3) and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM) compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH)(2)D(3). Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Songqing
authors.initials: S
authors.lastname: Na
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Ma
authors.forename: Jingyong
authors.initials: J
authors.lastname: Zhao
authors.forename: Clint
authors.initials: C
authors.lastname: Schmidt
authors.forename: Qing Q
authors.initials: QQ
authors.lastname: Zeng
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.forename: William W
authors.initials: WW
authors.lastname: Chin
authors.forename: Sunil
authors.initials: S
authors.lastname: Nagpal