1-(Arylpiperazinylamidoalkyl)-pyrimidones: orally active inhibitors of lipoprotein-associated phospholipase A(2).

The lipophilic 1-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, inhibitors of recombinant lipoprotein-associated phospholipase A(2), has been modified to give inhibitors of high potency in human plasma and enhanced physicochemical properties. Phenylpiperazineacetamide derivative 23 shows very promising oral activity.

The identification of a potent, water soluble inhibitor of lipoprotein-associated phospholipase A2.

Modification of the pyrimidone 5-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, lipophilic inhibitors of lipoprotein-associated phospholipase A2, has given inhibitors of nanomolar potency and improved physicochemical properties. Compound 23 was identified as a potent, highly water soluble. CNS penetrant inhibitor suitable for intravenous administration.

N-1 substituted pyrimidin-4-ones: novel, orally active inhibitors of lipoprotein-associated phospholipase A2.

From two related series of 2-(alkylthio)-pyrimidones, a novel series of 1-((amidolinked)-alkyl)-pyrimidones has been designed as nanomolar inhibitors of human lipoprotein-associated phospholipase A2. These compounds show greatly enhanced activity in isolated plasma. Selected derivatives such as compounds 51 and 52 are orally active with a good duration of action.

Natural product derived inhibitors of lipoprotein associated phospholipase A2, synthesis and activity of analogues of SB-253514.

The synthesis of analogues of SB-253514, a novel natural product derived inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), is described together with their ability to inhibit Lp-PLA2.

Non-thiazolidinedione antihyperglycaemic agents. Part 3: The effects of stereochemistry on the potency of alpha-methoxy-beta-phenylpropanoic acids.

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARgamma (peroxisomal proliferator activated receptor gamma), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

Inhibition of herpes proteases and antiviral activity of 2-substituted thieno[2,3-d]oxazinones.

Cinnamyl derivatives of thieno[2,3-d]oxazinones are mechanism-based inhibitors of the HSV-2, VZV and CMV herpes proteases which demonstrate nanomolar potency. Compounds 5 and 28 inhibit protease processing in HSV-2 infected cells with a selectivity index of at least 30.

Inhibition of human cytomegalovirus protease by enedione derivatives of thieno[2,3-d]oxazinones through a novel dual acylation/alkylation mechanism.

Enedione derivatives of thieno[2,3-d]oxazinones are nanomolar inhibitors of CMV protease which act through a novel dual acylation of the catalytic serine and alkylation of the protease cysteine 161 via a Michael addition to the enedione moiety of the inhibitor.

[Dental caries prevention with semestral topical administration of acidulated phosphate fluoride]. / Prevenção da cárie dental com aplicações tópicas semestrais de flúor-fosfato acidulado.

998 children aged 6, 8 and 10, from low income families living in the Federal District, Brazil and attending public, first grade, schools, received bi-annual topical APF Gel-Tray applications. The mass methodology proposed by the National Dental Caries Preventive Program of the Brazilian Ministry of Health, without previous prophylaxis, was adopted. After one year, in fluoridated communities the reduction in the incidence of CPOS was of 31.6%, 24.9% and 39.5%, respectively, for the groups aged 6, 8 and 10. In non fluoridated communities the reductions were, respectively, of 24.3%, 26.6% and 27.7%, in every case with statistic significance at the 95% confidence level. Considering the positive results in a developing area, it is recommended that oral health institutions at all levels could adopt a comprehensive and continuous preventive program for children under their responsibility.

Relaxant activity of 6-cyano-2,2-dimethyl-2H-1-benzopyran-4-carboxamides and -thiocarboxamides and their analogues in guinea pig trachealis.

Structural modifications of the potassium channel activator cromakalim (1) are described in which the amide moiety at C-4 has been replaced by carboxamide and thiocarboxamide functions. Analogues in which the hydroxyl group at C-3 has been oxidized or removed are also disclosed. Such analogues display an interesting profile of smooth muscle relaxant activity in the guinea pig isolated trachea, not all of which appears to result from the opening of potassium channels, but few compounds retain useful in vivo activity. However, one compound in particular, 6-cyano-2,2-dimethyl-N-methyl-2H-1-benzopyran-4-thiocarboxamide (13) was shown to be a potent potassium channel activator in vitro and to provide prolonged protection to guinea pigs from the respiratory effects of inhaled histamine.

Synthesis and smooth muscle relaxant activity of a new series of potassium channel activators: 3-amido-1,1-dimethylindan-2-ols.

The synthesis of a novel series of smooth muscle relaxants which have been shown to act via the opening or activation of potassium channels is described. Compounds have been evaluated for their ability to inhibit spontaneous tone in guinea pig isolated trachealis and structure-activity relationships are discussed. One compound in particular, 1,1-dimethyl-5-nitro-3-(2-pyridon-1-yl)indan-2-ol, (16) was identified as a potent relaxant of airways smooth muscle in vitro with IC50 = 0.15 microM and was found to significantly inhibit histamine-induced dyspnoea in conscious guinea pigs when given orally 30-45 min prior to challenge.

Relaxant activity of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans on guinea pig isolated trachealis.

A series of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans related to the potassium channel activator cromakalim have been prepared and evaluated for their relaxant activity in guinea pig isolated tracheal spirals. Several analogues show enhanced relaxant activity relative to cromakalim in this preparation and the rank order of potency for those substituents investigated at C-6 was CF3 greater than CN greater than C2H5 greater than aza greater than or equal to CH3. One compound, trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-7-(trifluor omethyl)-2H- 1-benzopyran-3-ol (24), was resolved into its two enantiomers and the activity was shown to reside essentially in the (+)-isomer, adding further support to the suggestion that the smooth muscle receptor for these potassium channel activators is stereoselective.