Synthesis and evaluation of benzo[b]thiophene derivatives as inhibitors of alkaline phosphatases.
Presence of basic calcium phosphate in knee joints of osteoarthritis patients could be prevented by inhibiting tissue non-specific alkaline phosphatase (TNAP) activity. Levamisole or the L stereoisomer of tetramisole (a known TNAP inhibitor) has been used as a treatment for curing rheumatoid arthritis but its therapeutical use is limited due to side effects. We report the synthesis and the TNAP inhibition property of benzo[b]thiophene derivatives, among which benzothiopheno-tetramisole and benzothiopheno-2,3-dehydrotetramisole, which could be involved in a drug therapy for osteoarthritis. Two water soluble racemic benzothiopheno-tetramisole and -2,3-dehydrotetramisole with apparent inhibition constants K(i)=85+/-6 microM and 135+/-3 microM (n=3) comparable to that of enantiomeric levamisole 93+/-4 microM were found. Several novel derivatives showed more pronounced inhibition properties towards intestinal alkaline phosphatase than TNAP.
Université de Lyon, Villeurbanne F-69622, France.
Lina
L
Li
Lei
L
Chang
Stéphane
S
Pellet-Rostaing
François
F
Liger
Marc
M
Lemaire
René
R
Buchet
Yuqing
Y
Wu
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013552:Swine; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013876:Thiophenes; C088015:benzothiophene; D000469:Alkaline Phosphatase