ABSTRACT
A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.
Subject(s)
Anticoagulants/pharmacology , Indans/pharmacology , Lactams/pharmacology , Thrombin/antagonists & inhibitors , Anticoagulants/chemical synthesis , Binding Sites , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indans/chemical synthesis , Inhibitory Concentration 50 , Lactams/chemical synthesis , Models, Molecular , Structure-Activity RelationshipABSTRACT
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
Squalestatins without either the hydroxy group at C-4 or the carboxylic acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These modifications were well tolerated for compounds with the 4,6-dimethyloctenoate ester at C-6 (S1 series). However in analogues without the C-6 ester (H1 series), removal of the C-4 hydroxy group gave compounds with reduced potency, whereas decarboxylation at C-3 resulted in a dramatic loss of SQS inhibitory activity. In comparison with S1 1, C-4 deoxyS1 3 and C-3 decarboxyS1 10 have shorter in vivo durations of action on the inhibition of hepatic cholesterol biosynthesis in rats. C-4 deoxyS1 3 retains good serum cholesterol-lowering ability in marmosets, while C-3 decarboxyS1 10 showed only a marginal effect even at high dose.
Subject(s)
Anticholesteremic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Tricarboxylic Acids/pharmacology , Animals , Anticholesteremic Agents/chemical synthesis , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Callithrix , Cholesterol/biosynthesis , Cholesterol/blood , Cholesterol/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Rats , Squalene/metabolism , Structure-Activity Relationship , Tricarboxylic Acids/chemical synthesis , Tricarboxylic Acids/chemistry , Tricarboxylic Acids/metabolismABSTRACT
A series of 7-[2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl]-3,5- dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin.
Subject(s)
Cholesterol/biosynthesis , Hydroxy Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Pyrroles/chemical synthesis , Carcinoma, Hepatocellular/metabolism , Humans , Hydroxy Acids/pharmacology , Liver Neoplasms/metabolism , Lovastatin/pharmacology , Molecular Structure , Pyrroles/chemistry , Pyrroles/pharmacology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Squalestatin 1 is a member of a novel family of fermentation products isolated from a previously unknown Phoma species (Coelomycetes). Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observed at a concentration of 12 +/- 5 nM (range of 4-22 nM). Squalestatin 1 inhibits cholesterol biosynthesis from [14C]acetate by isolated rat hepatocytes (50% inhibition at 39 nM) and by rat liver in vivo. In marmosets, a species with a lipoprotein profile similar to that of man, squalestatin 1 lowers serum cholesterol by up to 75%. This compound will allow further investigation of the control of the sterol biosynthesis pathway and could also lead to the development of new therapies for elevated serum cholesterol.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Bridged Bicyclo Compounds/pharmacology , Cholesterol/blood , Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Tricarboxylic Acids/pharmacology , Animals , Apolipoprotein A-I/metabolism , Apolipoproteins B/blood , Callithrix , Cells, Cultured , Cholesterol/biosynthesis , Farnesyl-Diphosphate Farnesyltransferase/metabolism , Liver/cytology , Liver/metabolism , Male , RatsABSTRACT
Three novel fungal metabolites 1-3 isolated from cultures of a Phoma sp. C2932, are potent and selective inhibitors of squalene synthase. Their structures have been determined by a combination of spectroscopic, X-ray crystallographic and chemical methods; these natural products incorporate the highly functionalised bicyclic core, [1S-(1 alpha, 3 alpha, 4 beta, 5 alpha, 6 alpha, 7 beta]-4,6,7-trihydroxy- 2,8-dioxabicyclo-[3.2.1]octane-3,4,5-tricarboxylic acid.