Inhibitors of cholesterol biosynthesis. 4. trans-6-[2-(substituted-quinolinyl)ethenyl/ethyl]tetrahydro-4-hydroxy-2 H-pyran-2-ones, a novel series of HMG-CoA reductase inhibitors.
A series of substituted quinoline mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and (cholesterol biosynthesis) in vivo. Since previous studies suggested that the 4-(4-fluorophenyl) and 2-(1-methylethyl) substituents afforded optimum potency, attention was focused on variations at position 6 of the quinoline ring. Biological evaluation of a small number of analogues bearing a variety of 6-substituents showed that modification at this position had little effect on potency. Several compounds (8b, 8e, and 11) were identified that showed comparable potency to compactin and mevinolin in both the in vitro and in vivo assays.
Sliskovic
D R
DR
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Picard
J A
JA
Roark
W H
WH
Roth
B D
BD
Ferguson
E
E
Krause
B R
BR
Newton
R S
RS
Sekerke
C
C
Shaw
M K
MK
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D011753:Pyrones; D011804:Quinolines