Inhibitors of cholesterol biosynthesis. 6. trans-6-[2-(2-N-heteroaryl-3,5-disubstituted- pyrazol-4-yl)ethyl/ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones.
A series of N-heteroaryl-substituted mevalonolactones were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase both in vitro and in vivo, and to lower plasma cholesterol in a hypercholesterolemic dog model. The goal of the strategy employed was to design an inhibitor which possessed the pharmacological properties of lovastatin (1), and the physicochemical properties (increased hydrophilicity) of pravastatin (2). Two compounds 20a and 20b, were more potent than lovastatin at inhibiting cholesterol biosynthesis both in vitro and in vivo. In terms of plasma cholesterol lowering, 20a was much more efficacious than lovastatin. In addition to possessing increased biological activity, these compounds are significantly less lipophilic than lovastatin, in fact, 20b has a CLOGP value comparable to pravastatin.
Sliskovic
D R
DR
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Blankley
C J
CJ
Krause
B R
BR
Newton
R S
RS
Picard
J A
JA
Roark
W H
WH
Roth
B D
BD
Sekerke
C
C
Shaw
M K
MK
Stanfield
R L
RL
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004285:Dogs; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D017035:Pravastatin / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; C074923:6-(2-(5-(4-fluorophenyl)-3-(1-methylethyl)-1-(2-pyridinyl)-1H-pyrazol-4-yl)ethenyl)tetrahydro-4-hydroxy-2H-pyran-2-one; C074924:6-(2-(5-(p-fluorophenyl)-3-(1-methylethyl)-1-(2-pyrazinyl)-1H-pyrazol-4-yl)ethenyl)tetrahydro-4-hydroxy-2H-pyran-2-one; D002784:Cholesterol; D008148:Lovastatin; D017035:Pravastatin