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 D(3) (1,25(OH)(2)D(3)), and a series of 2-methylene-19-nor analogs of 1,25(OH)(2)D(3) 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.
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Nirca J
NJ
Nieves
Jamie M
JM
Ahrens
Lori A
LA
Plum
Hector F
HF
DeLuca
Margaret
M
Clagett-Dame
D000152:Acne Vulgaris / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects; D004100:Dihydroxycholecalciferols / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D004872:Ergocalciferols / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D017488:Hyperkeratosis, Epidermolytic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D007536:Isomerism; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008817:Mice, Mutant Strains
C426833:19-nor-1,24,25-trihydroxyvitamin D2; C519954:2-methylene-19-nor-(20S)-1alpha,25-dihydroxyvitamin D3; D004100:Dihydroxycholecalciferols; D004872:Ergocalciferols; D002117:Calcitriol; C521167:2-methylene-19-nor-(20S)-1 alpha-hydroxy-bishomopregnacalciferol; D002118:Calcium