Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones.

Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC-MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2-7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with Kms ranging from 7 to 160 µM and turnover numbers of 30-40 min(-1). The product formed was identified by LC-MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.

1-Arylsulfonyl-2-(pyridylmethylsulfinyl) benzimidazoles as new proton pump inhibitor prodrugs.

New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition.

Bimatoprost, prostamide activity, and conventional drainage.

PURPOSE: Despite structural similarity with prostaglandin F(2 alpha), the ocular hypotensive agent bimatoprost (Lumigan; Allergan, Inc., Irvine, CA) shows unique pharmacology in vitro and functional activity in vivo. Unfortunately, the precise mechanisms that underlie bimatoprost's distinctive impact on aqueous humor dynamics are unclear. The purpose of the present study was to investigate the effects of bimatoprost and a novel prostamide-selective antagonist AGN 211334 on human conventional drainage. METHODS: Two model systems were used to test the consequences of bimatoprost and/or AGN 211334 treatment on conventional drainage. Human anterior segments in organ culture were perfused at a constant flow rate of 2.5 microL/min while pressure was recorded continuously. After stable baseline facilities were established, segments were treated with drug(s), and pressure was monitored for an additional 3 days. In parallel, the drugs' effects on hydraulic conductivity of human trabecular meshwork (TM) cell monolayers were evaluated. Pharmacological properties of AGN 211334 were characterized in isolated feline iris preparations in organ culture and heterologously expressed G-protein-coupled receptors were examined in vitro. RESULTS: Bimatoprost increased outflow facility by an average of 40% +/- 10% within 48 hours of treatment (n = 10, P < 0.001). Preincubation or coincubation with AGN 211334 significantly blunted bimatoprost's effects by 95% or 43%, respectively. Similar results were obtained in cell culture experiments in which bimatoprost increased hydraulic conductivity of TM cell monolayers by 78% +/- 25%. Pretreatment with AGN 211334 completely blocked bimatoprost's effects, while coincubation decreased its effects on average by 74%. In both models, AGN 211334 alone significantly decreased fluid flux across trabecular tissues and cells. CONCLUSIONS: The findings indicate that bimatoprost interacts with a prostamide receptor in the trabecular meshwork to increase outflow facility.

Studies of the condensation of sulfones with ketones and aldehydes.

[reaction: see text] The condensation of ketones or aldehydes with sulfones was shown to give a variety of products. Condensation of 2-methylcyclohexanone with dimethyl sulfone using potassium t-butoxide as base gave useful yields of 1,2-dimethylenecyclohexane. Under the same conditions, cycloheptanone, 3-methyl-2-butanone, and 2-butanone were converted to dienes. Remarkably, these reaction conditions converted acetophenone into p-terphenyl (10%) and (E)-1,4-diphenyl-3-penten-1-one (44%). Propiophenone was converted to 2'-methyl-p-terphenyl (61%). Using alpha-tetralone produced 1-methynaphthalene and naphthalene. No reaction took place with beta-tetralone. Using diethyl sulfone with alpha-tetralone lead to pure naphthalene. Condensation of isobutyraldehyde and dimethyl sulfone using potassium t-butoxide gave isoprene in low yield. Using benzaldehyde and benzyl phenyl sulfone in N,N-dimethylacetamide gave 1,2-diphenyl-1-phenylsulfonylethylene, N,N-dimethylcinnamide, and a complex condensation product. Only 1,2-diphenyl-1-phenylsulfonylethylene was obtained when the solvent was THF.

A convenient synthesis of 7-halo-1-indanones and 8-halo-1-tetralones.

A regioselective oxidation of N-indan-4-yl-acetamide or N-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamide with potassium permanganate followed by acidic hydrolysis gave 7-aminoindan-1-one or 8-aminotetral-1-one in good yield. The amino ketones were converted to the corresponding 7-haloindanone or the 8-halotetralone. Another method to prepare 7-haloindan-1-ones was completed by a cyclization of 3-chloro-1-(2-halophenyl)propan-1-one under Friedel-Crafts conditions to produce the product in gram quantity.