Selective protection and relative importance of the carboxylic acid groups of zaragozic acid A for squalene synthase inhibition.
Chemistry that allows selective modification of the carboxylic acid groups of the squalene synthase inhibitor zaragozic acid A (1) was developed and applied to the synthesis of compounds modified at the 3-,4-,5-,3,4-,3,5-, and 4,5-positions. A key step in this procedure is the selective debenzylation by transfer hydrogenolysis in the presence of other olefinic groups. These compounds were tested in the rat squalene synthase assay and in vivo mouse model. Modification at C3 retains significant enzyme potency and enhances oral activity, indicating that C3 is not essential for squalene synthase activity. Modification at C4 and C5 results in significant loss in enzyme activity. In contrast, substitution at C3 or C4 enhances in vivo activity. Furthermore, disubstitution at the C3 and C4 positions results in additive in vivo potency.
Biftu
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Merck Research Laboratories, Rahway, New Jersey 07090.
Acton
J J
JJ
Berger
G D
GD
Bergstrom
J D
JD
Dufresne
C
C
Kurtz
M M
MM
Marquis
R W
RW
Parsons
W H
WH
Rew
D R
DR
Wilson
K E
KE
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002264:Carboxylic Acids / Q000737:chemistry*; D004951:Esterification; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D014233:Tricarboxylic Acids / Q000737:chemistry* / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002264:Carboxylic Acids; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D013186:Farnesyl-Diphosphate Farnesyltransferase