Robert E. Damon

Phosphonate-containing analogs of cholesteryl ester as novel inhibitors of cholesteryl ester transfer protein

Abstract A series of phosphorus-containing analogs of cholesteryl ester have been synthesized as potential inhibitors of cholesteryl ester transfer protein (CETP). The most potent inhibitor, phosphonate 7 , represents a novel inhibitor of CETP.

Triterpene and diterpene inhibitors of pyruvate dehydrogenase kinase (PDK).

Several oximes of triterpenes with a 17-beta hydroxyl and abietane derivatives are inhibitors of pyruvate dehydrogenase kinase (PDK) activity. The oxime 12 and dehydroabietyl amine 2 exhibit a blood glucose lowering effect in the diabetic ob/ob mouse after a single oral dose of 100 micromol/kg. However, the mechanism of the blood glucose lowering effect is likely unrelated to PDK inhibition.

Acetylenic Amides. I. Synthesis of N-Substituted-2-propynamides

Abstract The efficient synthesis of N-substituted-2-propynamides was accomplished by three methods; the reaction of amines with either the N-hydroxysuccinimide ester or mixed anhydride of propiolic acid, or by the interaction of lithiotrimethylsilylacetylene with isocyanates followed by desilation with fluoride.

Correlation of oxidation potential and toxicity in thiobenzamides

Abstract The oxidation potentials of a series of 4-substituted thiobenzamides (1) were measured by linear sweep voltammetry. When compared with the known toxicological values for these compounds it was found that there is a direct correlation between oxidation potential and toxicity.

Thiourea-based gemfibrozil analogues as HDL-elevating agents.

A series of gemfibrozil analogues with a thiourea moiety embedded in the side chain was prepared and evaluated as HDL-elevating agents. Derivatives 8b, 9b, 9c, and 9d were found to be approximately as effective as gemfibrozil (1) for HDL cholesterol elevation.

Design and biological evaluation of a series of thiophene-based 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors

Abstract A series of highly functionalized thiophene-based 3,5-dihydroxyheptenoic acid derivatives (10) were prepared from aldehydes 6 by homologation, aldol condensation with ethyl acetoacetate dianion and stereoselective β-hydroxyketone reduction. High levels of HMG-CoA reductase inhibitory activity have been found within the series. The most active analog in vitro was 10i whereas in vivo, 10e, 10i, 10m, 10n, 10o, and 10v were approximately equipotent.

SQUALENE SYNTHASE INHIBITORS : ISOSTERIC REPLACEMENTS OF THE FARNESYL CHAIN OF BENZYL FARNESYL AMINE

Abstract Squalene synthase catalyzes the committed step of cholesterol biosynthesis. We report here the synthesis and in vivo activity of a series of squalene synthase inhibitors that contain isosteric replacements for the farnesyl chain of the known inhibitor benzyl farnesyl amine.

SYNTHESIS OF A CON FORMATIONALLY RESTRAINED 4-ARYLTHIOPHENE-3-HEPTENOIC ACID AND ITS EVALUATION AS AN HMG COENZYME A REDUCTASE INHIBITOR

A 4-phenylthiophene tethered to the 5-position of the heterocycle was synthesized from 1benzosuberone. The key steps in the synthesis were the tandem thiolacetate hydrolysis Michael addition intramolecular Wittig reaction (5 -> 2) and the chelation-controlled reduction of the hydroxy ß-ketoester (12 —> 13). The product 14 exhibited nearly identical in vivo potency to the non-tethered analogs. Introduction Coronary heart disease remains one of the leading causes of death in western civilization. Elevated levels of serum cholesterol, and in particular, low density lipoprotein (LDL) cholesterol are strongly correlated with risk of morbidity and mortality due to this disease (1-3). The primary defense against elevated LDL cholesterol levels is dietary intervention. However, for patients nonresponsive to this intervention pharmacological treatment is indicated. The goal of developing safe and effective therapeutic agents to lower LDL-cholesterol has focused primarily on inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase, the key enzyme which catalyzes the conversion of HMG-CoA to mevalonic acid in the cholesterol biosynthetic pathway. A variety of HMG-CoA reductase inhibitors with a common eryiAro-ß^dihydroxyheptenoic acid motif have been reported (4). We recently described the design and biological evaluation of a series of highly functionalized thiophene-based 3,5-dihydroxyheptenoic acid derivatives (D as inhibitors of HMG-CoA reductase (5). Within this series of compounds we found that the in vitro activity was generally higher when the substituent R2 at C-4 of the thiophene ring was a phenyl group (either substituted or unsubstituted). The biological activity was less sensitive to the nature of the substituent Ri at C-5. Groups such as phenyl, alkenyl, or small alkyl moieties like methyl or isopropyl were tolerated. With this data in hand we wished to investigate the effect of tethering the phenyl group at C-4 to the C-5 position of the thiophene ring which would effectively rigidify the conformation of the phenyl with respect to the plane of the thiophene heterocycle (2). We initially considered a one, two, or three-carbon chain as likely candidates, however, we ruled out the one-carbon (CH2) analog which would possess a highly oxidizable methylene unit between two aromatic groups. The next higher homolog, the two-carbon (CH2CH2) analog was also ruled out for synthetic reasons. The conditions used for the aromatization of the thiophene ring (Scheme 1,