Novel vitamin D3 antipsoriatic antedrugs: 16-En-22-oxa-1alpha,25-(OH)2D3 analogs.
A series of 16-en-22-oxa-derivatives of vitamin D3 based on the structure of maxacalcitol (2) were prepared. Maxacalcitol is currently used topically for the treatment of psoriasis and is recognized as the most successful antedrug of natural vitamin D(3) because it retains the original antiproliferative activity of calcitriol without increased calcemic activity. We introduced 16-olefinic functionality to accelerate the oxidative metabolism of the drug in liver, presumed to be essential for the reduction of calcemic activity, and modified the side-chain moiety by placing the 22-oxygen on the more labile allylic carbon center. Novel 22-oxa analogs (7a-i), carrying either the 24-alkynyl bond or 24-hydroxy functionality in addition to the 16-double bond were synthesized and their pharmacokinetics were evaluated.
Shimizu
Kazuki
K
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. tazumikzk@chugai-pharm.co.jp
Kawase
Akira
A
Haneishi
Tsuyoshi
T
Kato
Yasuharu
Y
Kobayashi
Takamitsu
T
Sekiguchi
Nobuo
N
Yamamoto
Tessai
T
Ishigai
Masaki
M
Tokuda
Kazuo
K
Matsushita
Tomochika
T
Shimaoka
Shin
S
Morikawa
Kazumi
K
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D011565:Psoriasis / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics
D014807:Vitamin D