Ryozo Sakoda

Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors

A series of quinoline-based 3,5-dihydroxyheptenoic acid derivatives were synthesized from quinolinecarboxylic acid esters by homologation, aldol condensation with ethyl acetoacetate dianion, and reduction of 3-hydroxyketone to evaluate their ability to inhibit the enzyme HMG-CoA reductase in vitro. In agreement with previous literature, a strict structural requirement exists on the external ring, and 4-fluorophenyl is the most active in this system. For the central ring, substitution on positions 6, 7, and 8 of the central quinoline nucleus moderately affected the potency, whereas the alkyl side chain on the 2-position had a more pronounced influence on activity. Among the derivatives, NK-104 (pitavastatin calcium), which has a cyclopropyl group as the alkyl side chain, showed the greatest potency. We found that further modulation and improvement in potency at inhibiting HMG-CoA reductase was obtained by having the optimal substituents flanking the desmethylmevalonic acid portion, that is, 4-fluorophenyl and cyclopropyl, instead of the usual isopropyl group.

Synthesis and biological evaluations of condensed pyridine and condensed pyrimidine-based HMG-CoA reductase inhibitors

A series of 3,5-dihydroxyheptenoic acid derivatives containing pyrazolopyridine, isoxazolopyridine, thienopyridine, and pyrazolopyrimidine as a key scaffold was synthesized from condensed pyridine and condensed pyrimidine carboxylic acid esters by homologation, aldol condensation with ethyl acetoacetate dianion, and stereoselective reduction of the 5-hydroxyketone. Several compounds in the series were found to have potent HMG-CoA reductase inhibitory activities in vitro and marked cholesterol biosynthesis inhibitory activities in vivo. It has been shown that these scaffolds can be used as a suitable replacement for the hexahydronaphthalene ring present in naturally occurring HMG-CoA reductase inhibitors.

First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104

First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104 are reported. A pair of syn diol isomers (NK-104 and its enantiomer) was obtained efficiently by diastereomeric resolution. The synthesis of a pair of anti diol isomers (3-epimer and 5-epimer) was accomplished effectively by the asymmetric aldol reaction followed by anti stereoselective reduction as key steps. Their purity determinations were effected by chiral HPLC analysis.

Potentiation of the Vincristine Effect on P388 Mouse Leukemia Cells by a Newly Synthesized Dihydropyridine Analogue, PAK‐200

A newly synthesized dihydropyridine analogue, 2‐[benzyl(phenyl)amino]ethyl 1,4‐dihydrb‐2,6‐dimethyl‐5‐(5,5‐dimethyl‐2‐oxo‐l,3,2‐dioxaphosphorinan‐2‐yl)‐l‐(2‐morpholinoethyl)‐4‐(3‐nitrophen‐yl)‐3‐pyridinecarboxylate (PAK‐200), at 1 μM completely reversed the resistance to vincristine in vincristine‐resistant P388 mouse leukemia cells (P388/VCR), in vitro. PAK‐200 at 2 μM inhibited the efflux of [3H]vincristine from P388/VCR and increased the accumulation of [3H]vincristine in P388/VCR to a level similar to that in P388 cells. P‐Glycoprotein in membrane vesicles from P388/ VCR cells was photolabeled with [3H]azidopine. The labeling was completely inhibited by 10 μM PAK‐200. The calcium antagonistic activity of PAK‐200 was about 1000 times lower than that of another dihydropyridine analogue, nicardipine. Experiments with P388 and P388/VCR‐bearing mice showed that PAK‐200 enhanced the effect of vincristine on both leukemia cells in vivo. These results suggest that PAK‐200 interacts with P‐glycoprotein and reverses drug resistance in P388 mouse leukemia cells in vitro, and that PAK‐200 has an ability to potentiate the effect of vincristine on P388 mouse leukemia cells in vivo.