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  • Acidic substituents showed moderate biochemical activity but


    Acidic substituents () showed moderate biochemical activity, but these compounds showed reduced cellular potency. Additional compounds bearing a carboxylic GNE-617 were also prepared and tested (data not shown). All of acidic compounds showed low cellular potency regardless of their biochemical activities. To confirm that the poor cellular potency was indicative of efficacy for these compounds, compound was assayed but showed poor efficacy in the IL-6 model. All basic amine substituents () showed high biochemical activity and cellular potency. Particularly, showed the highest CSF-1R activity (IC = 4.4 nM) of all tested compounds and showed the highest cellular potency among the amine series (IC = 29 nM). Most compounds exhibited relatively high solubility (2.4–81.4 μM) and high efficacy. In addition, the efficacy of the most basic compounds were persistent despite showing low S9 metabolic stability in rat and mouse. In particular, the three compounds (–) showed excellent persistence effect (about 80 %inhibition in 6 h). We assumed that a clinical candidate could be selected from these compounds. Meanwhile, it is well known that strongly basic and high lipophilic compounds offer concerns about toxicity such as phospholipidosis and hERG. Therefore, we had introduced relatively weakly basic and low lipophilic parts such as GNE-617 shown in . The Values of calculated log P and Basic pKa were shown in . Actually, compounds – showed the low hERG inhibition (The IC values of , , and were >10 μM, >3 μM, and >3 μM, respectively). However, the development studies of the three compounds were halted due to phospholipidosis in toxic study (the result is not shown in this report). All neutral hydroxyl substituents (, , and ) showed high biochemical activity and cellular potency. The mono-alcohol compounds () showed less efficacy. Since solubility of compounds , (R = Et and cyclopropyl) were very poor, we introduced di-ol units at R to improve solubility. Improvements in solubility were achieved by introducing glycerol derivatives ( and (3–8-fold)) and propane-1,3-diol ( (6-fold)) when R was fixed as cPr. Since an introduction of di-ol derivatives improved the solubility, we thought that introducing tri-ol could improve solubility additionally. However tri-ol derivatives (, did not improve more than we expected (2–3-fold). Concerning to cellular potency, ()-, ()-, and showed the highest values (The IC values were 20 nM, 21 nM, and 15 nM, respectively) among all compounds. Six compounds ((), () (), and ) showed high efficacy. Only three of six compounds (() (), and ) showed sufficient persistence after oral administration (>50 %inhibition at 6 h). The efficacy and persistence effect for the enantiomers (()- vs. ()- and ()- vs. ()-) differed despite the S9 metabolic stability of them were almost the same. The reason was presumed to be concerned with conjugated metabolism. Actually, the phosphate conjugation with terminal hydroxyl group was detected as the major metabolite from the metabolite search experoments for ()- () (data not shown). Also, the phosphate conjugation cannot be produced by liver S9 and there is a possibility that the conjugated metabolic activities differs between the enantiomers. Therefore, we considered that efficacy and persistence effect for the enantiomers made differences because of the differences of the cojugated metabolic activities. Since (), (), and showed sufficient persistence effect, these neutral compounds were expected as clinical candidates. Furthermore, PK properties of these compounds were investigated in order to predict pharmacokinetics in human, as shown in . In rat, the bioavailability of these compounds were equally good, although the oral exposure of () was the highest (Cmax = 0.74 μM, AUC = 4.15 μM*h) at 3 mg/kg PO. On the other hand, PK values in monkey differed from the case of rat. () exhibited the best profiles for the pathological animal model, which were T, Vd, and MRT (T = 13.4, Vd = 5.00, MRT = 7.5) at 1 mg/kg i.v. as indexes of continuity. Consequently, () was thought to be the most promising compound.