Ronald B. Gammill

U-73482 : a novel ACAT inhibitor that elevates HDL-cholesterol, lowers plasma triglyceride and facilitates hepatic cholesterol mobilization in the rat

U-73482, a novel acylCoA:cholesterol acyltransferase (ACAT) inhibitor with systemic activity, has been evaluated for its effects on a variety of lipid metabolic parameters in the rat. The compound inhibits ACAT in vitro in cultured Fu5AH rat hepatoma cells and demonstrates systemic activity through inhibition of hepatic ACAT in rats receiving the drug orally. U-73482 also lowers plasma triglycerides at 40 mg/kg per day in the rat and elevates high density lipoprotein cholesterol (HDL-chol) in a dose-related fashion over the range of daily intakes of 0-40 mg/kg in the rat. Elevations in HDL-chol are followed by elevations in total plasma cholesterol in normal rats but the compound exerts hypocholesterolemic activity in cholesterol-fed rats and promotes clearance of stored hepatic sterol in rats pretreated with a hypercholesterolemic diet and then changed over to normal chow. The triglyceride-lowering and HDL-chol elevating effects of U-73482 coupled with its ability to promote tissue sterol clearance and block the hypercholesterolemic effects of dietary cholesterol in animals, suggests that the compound has potential as a therapeutic agent for treatment of lipid disorders in man.

Conformationally restricted P1-P1' transition state analogues. Synthesis of 1(R), 3(R) [1(S), 2(S)] and 1(S), 3(S) [1(S), 2(S)] 3-[3-cyclohexyl-2-[(BOC)amino]-1-hydroxypropyl]-2,2-dimethylcyclo propane carboxylic acids

Abstract A concise synthesis and determination of absolute stereochemistry of two novel diastereomeric cyclopropyl containing transition state mimics is described.

Catalytic osmylation and oxypalladation of khellin. Two useful methods for furan ring degradation. Replacement of the furan ring by an isoxazole ring.

Abstract Two oxidation reactions are described which result in the selective degradation of the furan ring in khellin. Conversion of these products to previously inaccessible analogues is described.

The synthesis of 2- and 3-fluorokhellin

Abstract The bromofluorination of khellin is described. The unique influence of fluorine is demonstrated in various substitution and elimination reactions leading ultimately to the preparation of both 2- and 3-fluorokhellin.

The addition of amines to 3-bromochromone and 6-bromofurochromone. An unexpected ring contraction of the pyrone ring.

Abstract Addition of amines to 3-bromochromone and 6-bromofurochromone results in a novel ring contraction of the pyrone ring.

A titanium (IV) mediated one-pot double condensation synthesis of 5,6-dihydro-4H-pyran-4-ones

Abstract An alternative method for the synthesis of 2-amino-5,6-dihydro-4H-pyran-4-ones and 5,6-dihydro-4H-pyran-4-ones is described. This preparation makes use of the condensation of titanium enolates derived from β-hydroxy ketones with phosgene iminium chloride or trimethylorthoformate, respectively. The in situ formation of the necessary titanium complex from an aldol condensation using simple ketone and aldehyde precursors makes for a one-pot double condensation synthesis of the desired dihydropyrones.

A novel asymmetric synthesis of atropisomeric 6-aryl pyrazinones via an unusual chirality transfer process. New chiral ligands for the GABAA/Chloride ionophore complex

Abstract Cyclization of ( S , S )- α -[(1-phenylethyl)amino]- α -(2-iodophenyl)acetonitrile 3a with (COCl) 2 in toluene or chlorobenzene afforeded the atropisomeric pyrazinone ( aS , S ) 6-(2-α-iodophenyl)-3,5-dichloro-1-(1-phenylethyl)-2(1H)-pyrazinone 7a in 57% yield. With smaller ortho substituents, mixtures of atropisomers were obtained. Stereochemical assignments were made via X-Ray and NOE experiments.

Evaluation of timefurone, a new anti-atherosclerotic drug, for its effects on lipoprotein cholesterol in male SEA Japanese quail and rats.

Timefurone was evaluated in several animal models for cholesterol-lowering and anti-atherosclerotic activity. In normal male rats, a dose-response study with timefurone (3, 10, 30, 50 and 100 mg/kg/day) was conducted for 7 days. Significant activity was observed only at 50 and 100 mg/kg/day, where very low and low density lipoprotein cholesterol [(VLDL + LDL)-C] and total-C levels were reduced (mean 27 and 20%). High density lipoprotein cholesterol (HDL-C) was lowered 24% by the high timefurone dose. Timefurone (10, 20, 50 and 100 mg/kg/day in the diet) was then examined in normocholesterolemic SEA japanese quail. beta-lipoprotein cholesterol (VLDL + LDL)-C was reduced at all doses (mean 58%), while alpha-lipoprotein cholesterol (HDL-C) was elevated by all doses of timefurone (mean 45%). Male weanling rats made moderately hypercholesterolemic represented a 3rd phase of timefurone (2.5, 5, 10, 20, 50, 100 mg/kg/day) testing. After 4 days of drug treatment, marked hypocholesterolemic activity was observed for (VLDL + LDL)-C (mean decrease 49%) and total-C (mean 33%). HDL-C levels were increased with 10 and 100 mg/kg/day doses. Timefurone (25 and 100 mg/kg/day in the diet) also caused a significant reduction in atherosclerotic development in hypercholesterolemic SEA japanese quail. Atherosclerotic involvement (determined by visual assessment of plaque), arterial weight, and arterial cholesterol (total and mg/g artery) were clearly lowered by both doses of timefurone. There was no evidence of significant drug toxicity in any of these experiments. On the basis of these data, timefurone has excellent therapeutic potential and additional study of the drugs hypocholesterolemic and anti-atherosclerotic properties appears warranted.

A novel entry to substituted chromones and furochromones through cyclopropane intermediates

Abstract Addition of several carbon nucleophiles to 3-bromochromone 1 and 6-bromofurochromone 2 yield interestingly substituted δ-pyrone ring analogues.

Total synthesis of khellinone and khellin the pyrogallol route regiospecific methoxylation of a benzofuran

Abstract Khellinone is prepared in 5 steps from the readily available triacetoxybenzofuran 7. The key step in the synthesis is a regiospecific oxidative methoxylation of benzofuran 9.