In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor.

1. We evaluated potential in vitro drug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively. 2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC50 value of 58.3 µM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72 hrs weakly induced CYP3A4 at a concentration of 10 µM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1-10 µM. 3. An in vitro transport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC50 value of 93.1 µM, but those for other transporters are greater than 100 µM. 4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters.

Imidazole derivatives as new potent and selective 20-HETE synthase inhibitors.

In a previous paper, we reported that an imidazole derivative 1 exhibited a potent inhibitory activity of 20-HETE synthase (1; IC(50) value of 5.7 nM), but this compound also exhibited little selectivity for cytochrome P450s (CYPs). We examined some derivatives of imidazole 1 which had an amino group on the side chain, and found that a dimethylaminohexyloxy derivative (3g; IC(50) value of 8.8 nM) showed potent and selective inhibitory activity.

Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.

In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral conditions and instability under acidic conditions. The instability of HET0016 in acidic conditions is due to the N-hydroxyformamidine moiety, which is considered to be essential for the potent and selective activity seen in our previous study. The activity was maintained when the N-hydroxyformamidine moiety was replaced by an imidazole ring (3a; IC(50) = 5.7 +/- 1.0 nM), but this was associated with a loss of selectivity for cytochrome p450s (CYPs). However, other azole derivatives such as isoxazole derivative 23 (IC(50) value 38 +/- 10 nM) and pyrazole derivative 24 (IC(50) value 23 +/- 12 nM) showed potent and selective activities with improved stability.