Linked Life Data

8246237

Source:http://linkedlifedata.com/resource/pubmed/id/8246237

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
1994-1-6
pubmed:abstractText
Compounds comprising a series of 7-[2-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-3,5- dihydroxy-6-heptenoic acid sodium salts (18) were synthesized and tested for their ability to inhibit HMG-CoA reductase in a partially purified enzyme preparation and cholesterol biosynthesis from acetate in cultured HEP-G2 cells. Changing the size of the saturated ring of the tetrahydroindazole nucleus did not improve potency, but incorporation of substituents at the 7-position resulted in up to 1700-fold improvement in inhibitory potency. Structure-activity studies revealed that the most potent compounds possess a substituted benzyl group at the 7-position, with a preference for steric bulk at the para position of the benzene ring. The most potent enzyme inhibitor (18t, IC50 = 3.0 nM) is approximately 3-fold more potent than lovastin sodium salt (2). The most potent cholesterol biosynthesis inhibitor in HEP-G2 cells (18q, IC50 = 0.078 microM) is slightly less potent than 2 (sodium salt). Molecular modeling studies suggested that, when compared to the parent compound (18b) lacking the appropriate 7-substituent, 18t overlaps better with 2 and literature inhibitors 5 and 6 in a hydrophobic binding region adjacent to the enzyme active site.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
36
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3674-85
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1993
pubmed:articleTitle
HMG-CoA reductase inhibitors: design, synthesis, and biological activity of tetrahydroindazole-substituted 3,5-dihydroxy-6-heptenoic acid sodium salts.
pubmed:affiliation
R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869.
pubmed:publicationType
Journal Article, Comparative Study