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Abstract. To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (I Kr ) prolonged action potential duration at 90% repolarization (APD 90 ) in a concentration-dependent manner, those showing Ca 2+ current (I Ca ) inhibition shortened APD 30 , and those showing Na + current (I Na ) inhibition decreased action potential amplitude (APA) and V max . Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD 90 , probably due to their blockade of I Na and / or I Ca , sometimes leading to a falsenegative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with I Kr -blocking activity prolonged APD 30-90 regardless of their I Na -and / or I Ca -blocking activities, suggesting that APD 30-90 is a useful parameter for evaluating the I Krblocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD 90 and APD 30-90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies. Supplementary material (Appendix): available only at http://dx

Abstract. Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayedrectifier potassium currents (I Kr ) and / or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on I Kr and / or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD 30-60 , APD 60-90 , and APD 30-90 , respectively) were calculated as the new parameters. All the 15 I Kr and / or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 ; and 8 of the 15 inhibitors prolonged APD 30-60 , APD 60-90 , and / or APD 30-90 more potently than APD 90 . The APD 30-60 , APD 60-90 , and APD 30-90 measurements revealed no difference in sensitivity when evaluating the effects of the I Kr and / or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD 30-60 , APD . Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD 30-60 , APD 60-90 , and APD 30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on I Kr and / or hERG currents. Supplementary material (Appendix): available only at http://dx

The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P and S1P, is described. While it has been revealed that the modulation of the S1P receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P over S1P and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED = 0.029 mg/kg, 24 h after oral dosing).