ABSTRACT
Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue 1b was observed only when this compound was dosed three times a day for 3 days.
Subject(s)
Anticholesteremic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Tricarboxylic Acids/metabolism , Tricarboxylic Acids/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Callithrix/metabolism , Cholesterol/biosynthesis , Cholesterol/blood , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Esters/chemical synthesis , Esters/pharmacology , Microsomes, Liver/enzymology , Molecular Structure , Rats , Tricarboxylic Acids/chemistryABSTRACT
A series of squalestatins modified at the C3-position with a heterocyclic functionality was prepared and evaluated in vitro as inhibitors of squalene synthase (SQS). Structure-activity relationships for compounds with the 4,6-dimethyloctenoate at C6(S1 analogues) were different from those for analogues lacking the C6 ester (H1 analogues), with a greater dependence on the nature of the C3-substituent for the H1 series. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. The C3-methyl ester derivative is 10-fold less active than H1, and SQS inhibitory activity similar to that of the methyl ester was retained only in those C3-heterocycle-substituted H1 analogues for which electrostatic potential maps of the C3-substituent were closely similar to that of a methyl ester.
