Structural and stereoelectronic requirements for the inhibition of mammalian 2,3-oxidosqualene cyclase by substituted isoquinoline derivatives.
2,3-Oxidosqualene lanosterol-cyclase (OSC; EC 5.4.99.7) is an attractive target for the design of compounds that block hepatic cholesterol biosynthesis. (4a alpha, 5 alpha, 6 beta, 8a beta)-Decahydro-5,8a-dimethyl-2-(1,5,9-trimethyldecyl)-6- isoquinolinol (1) and simplified analogs have been devised to inhibit this enzyme by mimicking the postulated pro-C-8 high-energy intermediary carbocation occurring during the cyclization-rearrangement pathway. In order to gain an understanding into the mechanism by which these types of molecules inhibit OSC, we have synthesized a series of substituted isoquinoline derivatives 3 and investigated the structural and stereoelectronic requirements, and their stringency, that make 3 potential high-energy intermediate analogs of OSC. Determination of the IC50 values of the different compounds with rat liver microsomal cyclase, allowed the study of the relative importance of (i) the nature and the stereochemistry of the nitrogen side chain, (ii) the presence of methyl groups at C-5 and C-8a (ring junction), (iii) the presence and stereochemistry of the C-6 hydroxyl group, (iv) the nature of the ring junction, and (v) the absolute configuration of the bicyclic system. The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors.
Barth
M M
MM
Laboratoires Fournier SCA, Daix, France.
Binet
J L
JL
Thomas
D M
DM
de Fornel
D C
DC
Samreth
S
S
Schuber
F J
FJ
Renaut
P P
PP
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D013185:Squalene / Q000031:analogs & derivatives / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C002821:2,3-oxidosqualene; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013185:Squalene; D002784:Cholesterol; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase