Carboxyl group-terminated polyamidoamine dendrimers bearing glucosides inhibit intestinal hexose transporter-mediated D-glucose uptake.

We are investigating non-absorbable polymeric conjugates bearing glucosides via a omega-amino triethylene glycol linker as oral anti-diabetic drugs that suppress an increase in the blood glucose level after meals through inhibition of Na(+)/glucose cotransporter (SGLT1). When the linker was bound to phloridzin, which is a SGLT1 inhibitor, to yield a precursor of the conjugate, the in vitro inhibitory effect on SGLT1-mediated d-glucose uptake was reduced to about one-tenth that of phloridzin. The inhibitory effect was recovered completely when the precursor was immobilized on the surface of poly(amidoamine) (PAMAM) dendrimers (generation: 3.0) by coupling with one-eighth or less of the terminal carboxyl groups. We considered that the phloridzin-derived glucose moiety on the dendrimer surface was prerequisite for SGLT1 inhibition but that the aglycon part was not always required for the inhibition. Commercially used arbutin, a SGLT1 substrate, was substituted for phloridzin whose aglycon is composed of toxic phloretin. The in vitro inhibitory effect of arbutin was about one-thirtieth that of intact phloridzin; however, the inhibitory effect of the PAMAM dendrimer-arbutin conjugates was as strong as that of the PAMAM dendrimer-phloridzin conjugates. Rat experiments further showed that the PAMAM dendrimer-arbutin conjugates significantly suppressed d-glucose-induced hyperglycemic effects. The dendritic conjugate bearing arbutin appears to be a good candidate as an oral anti-diabetic drug.