Identification of a Unique Subset of 2-Methylene-19-Nor Analogs of Vitamin D with Comedolytic Activity in the Rhino Mouse

The active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and a series of 2-methylene-19-nor analogs of 1,25(OH)2D3 were evaluated for their ability to reduce the size of utricles (comedolytic activity) in a rhino mouse model of acne. All analogs tested, as well as the native hormone, increased the skin epidermal thickness. In contrast, only a subset of analogs that lacked a full side chain and 25-hydroxyl group were found to possess comedolytic activity. A reduction in comedone area could be achieved without adversely affecting serum calcium levels. Although all compounds that contained a side chain ranging from 2 to 5 carbons in length had similar potency as comedolytic agents, increasing the length of the side chain resulted in a progressive increase in calcemic liability. Dose–response studies of the comedolytic analogs showed that an increase in epidermal thickness was achieved at a lower dose than that needed to induce comedolysis. Thus, we have identified a unique subset of vitamin D analogs that produce comedolysis in the absence of hypercalcemia. Further, the activity of vitamin D analogs in causing epidermal hyperproliferation has been distinguished from that resulting in a reduction in utricle size.