Synthesis of 4 alpha-(2-propenyl)-5,6-secocholestan-3 alpha-ol, a novel B-ring seco analog of the hypocholesterolemic agent 4 alpha-(2-propenyl)-5 alpha-cholestan-3 alpha-ol.
4 alpha-(2-Propenyl)-5 alpha-cholestan-3 alpha-ol (LY295427) was previously identified from a CHO cell-based assay to be a potent LDL receptor up-regulator and had demonstrated to be an effective agent in lowering plasma cholesterol levels in hypercholesterolemic hamsters. In order to investigate the effect of flexibility of the 3 alpha-hydroxy-bearing A-ring on the activity, 4 alpha-(2-propenyl)-5,6-secocholestan-3 alpha-ol (11), a B-ring seco analog of LY295427, is thus synthesized from cholest-4-en-3-one. Test results indicate that 11 is not active in the CHO cell-based LDL receptor/luciferase assay at concentrations up to 20 micrograms/mL. The result underlines the importance of maintaining the A-B-C-D ring rigidity of the 3 alpha-sterols in terms of binding to the putative oxysterol receptor.
Lin
H S
HS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Rampersaud
A A
AA
Richett
M E
ME
Beavers
L S
LS
McClure
D B
DB
Gadski
R A
RA
D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D004083:Cholestanol / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D002777:Cholestanols / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002783:Cholestenones / Q000378:metabolism; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006888:Hydroxycholesterols / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011973:Receptors, LDL / Q000096:biosynthesis / Q000235:genetics; D013329:Structure-Activity Relationship
C113842:2-propenyl-5,6-secocholestan-3-ol; D000924:Anticholesteremic Agents; D002777:Cholestanols; D002783:Cholestenones; D006888:Hydroxycholesterols; C107473:LY 295427; D011973:Receptors, LDL; C000475:cholest-4-en-3-one; C007997:25-hydroxycholesterol; D004083:Cholestanol; D008156:Luciferases