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Synthesis and evaluation of benzo[b]thiophene derivatives as inhibitors of alkaline phosphatases.

Bioorganic & medicinal chemistry (2009-09-29)
Lina Li, Lei Chang, Stéphane Pellet-Rostaing, François Liger, Marc Lemaire, René Buchet, Yuqing Wu
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Levamisol hydrochloride, VETRANAL®, analytical standard
Sigma-Aldrich
(−)-Tetramisole hydrochloride, ≥99% (GC)