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.
Suzuki
M
M
Central Research Institute, Nissan Chemical Industries, Ltd, Funabashi, Chiba, Japan. suzukimi@nissanchem.co.jp
Iwasaki
H
H
Fujikawa
Y
Y
Sakashita
M
M
Kitahara
M
M
Sakoda
R
R
D000284:Administration, Oral; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D002784:Cholesterol