Biomedical subjects

L A Gómez

Publications and source records attributed to L A Gómez.

10 recordsLinked to original sources

PubMed2001

Synthesis and SAR of a new series of COX-2-selective inhibitors: pyrazolo[1,5-a]pyrimidines.

The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.

Animals↗

PubMed2000

Determination of oxalate, sulfate and nitrate in honey and honeydew by ion-chromatography.

An ion chromatographic method for determining the anions oxalate, sulfate and nitrate in honey and honeydew samples is described. To prevent matrix interference and to isolate the anions a clean-up step using solid-phase extraction on anionic cartridges and eluting with a 0.01 M chromate solution is recommended. The anions are separated on an anionic column with a mobile phase of borate-gluconate buffer and using conductimetric detection. The method is applied to the analysis of samples from different botanical origin.

Calibration↗

PubMed1997

Synthesis and structure-activity relationship of a new series of potent AT1 selective angiotensin II receptor antagonists: 5-(biphenyl-4-ylmethyl)pyrazoles.

The synthesis and pharmacological activity of a new series of 5-(biphenyl-4-ylmethyl)pyrazoles as potent angiotensin II antagonists both in vitro (binding of [3H]AII) and in vivo (iv, inhibition of AII-induced increase in blood pressure, pithed rats; po, furosemide-treated sodium-depleted rats) are reported. The various substituents of the pyrazole ring have been modified taking into account the receptor's requirements derived from related structure-activity relationship studies. A propyl or butyl group at position 1 as well as a carboxylic acid group at position 4 were shown to be essential for high affinity. Different groups at position 3 (H, small alkyl, phenyl, benzyl) provided good binding affinity, but oral activity was highly discriminating: bulky alkyl groups provided the highest potencies. Among the acidic isosteres tested in the biphenyl moiety, the tetrazole group proved to be the best. Compound 14n (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l] methyl]-1H-pyrazole-4-carboxylic acid, UR-7280) shows high potency both in vitro (IC50 = 3 nM) and in vivo (iv, 61.2 +/- 10% decrease in blood pressure at 0.3 mg/kg; po, 30 mmHg fall in blood pressure at 0.3 mg/kg), in comparison to losartan (IC50 = 59 nM; iv, 62.5 +/- 8.9% decrease in blood pressure at 1 mg/kg; po, 13 mmHg fall in blood pressure at 3 mg/kg). These data, together with the good pharmacokinetic profile of 14n in different species, have led to its selection for clinical evaluation as an antihypertensive agent.

Angiotensin I↗

PubMed1996

Diphenylpropionic acids as new AT1 selective angiotensin II antagonists.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

Administration, Oral↗

PubMed1995

Decrease in actin gene expression in melanoma cells compared to melanocytes is partly counteracted by BrdU-induced cell adhesion and antagonized by L-tyrosine induction of terminal differentiation.

Malignant transformation is frequently accompanied by changes in the cytoarchitecture of adherent cells, which may be influenced by fluctuations in actin gene expression. We now show that normal melanocytes express a 5 fold higher level of actin mRNA than their melanoma counterparts. Induction of terminal melanogenesis did not increase actin in melanoma cells. However, culture with the thymidine analog, Bromodeoxyuridine, increased actin expression in undifferentiated but not in differentiating melanoma. Cell detachment assays and cell shape comparisons revealed a direct correlation of actin mRNA with increased melanoma cell adhesion rather than with differentiation-mediated suppression of tumor growth.

Actins↗

PubMed1993

2,2-Dialkylnaphthalen-1-ones as new potassium channel activators.

A new series of 2,2-dialkylnaphthalen-1-one potassium channel activators has been prepared, and their in vitro relaxant activities in isolated rat portal vein and guinea pig tracheal spirals as well as their oral antihypertensive effect in spontaneously hypertensive rats have been evaluated. The group of 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethylnaphthalen -1- ones with an electron-withdrawing substituent at the 6-position contain the most active compounds and 1,2-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2,2-dimethyl-1-oxonaphtha lene-6- carbonitrile, 17f (UR-8225), has been selected for further pharmacological development.

Animals↗

PubMed1992

Antibodies as molecular probes in neurobiology. Identification of chemically defined neurons and synapses in tissues and tissue cultures.

Immunocytochemical localization of 5-hydroxytryptamine (5-HT) in the nervous system and aggregate tissue cultures was performed employing an antibody to 6-OH-1,2,3,4-tetrahydro-beta-carboline. A number of immunochemical and biochemical tests with the antigen and the antibody and some procedural changes in the methodology applied for immunolocalization revealed the anti-5-HT-like affinity of the antibody, if applied in paraformaldehyde-fixed tissues. Studies in the hypothalamus, striatum, brainstem, spinal cord, and pineal gland show the complexities of the serotoninergic system. Ultrastructural immunocytochemistry with the preembedding technique reveals that 5-HT synapses are of the asymmetric type. The presynaptic element contains clear, round, small vesicles, with some large dense-core vesicles. The contacts are made with the somata and primary, secondary dendrites or with spines of non-5-HT neurons. Presynaptic dendrites are found in the n. raphe dorsalis, contacting non-5-HT dendrites. Double immunocytochemical methods demonstrated contacts of 5-HT fibers on enkephalin containing neurons of the spinal trigeminal nucleus and on somatostatin containing neurons of the medullary reticular formation. In vitro studies of cultured mesencephalic neurons were performed with the method of aggregating cultures. Such development of a miniature organized nerve tissue was followed up to 35 d in culture. Organization of the neuropil and synaptogenesis was studied using standard electron microscopy. The differentiation of neurons and astrocytes was studied using antibodies to 5-HT and GFAP. Serotonin immunoreactivity could be observed in neuronal bodies and processes at light microscope level as early as the fourth day of culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Effects of PAF-antagonists in mouse ear oedema induced by several inflammatory agents.

1. Several platelet activating factor (PAF)-antagonists of different chemical structures were tested in the arachidonic acid-, tetradecanoylphorbol acetate-, dithranol-, and benzoic acid-induced mouse ear oedema models. 2. Topical application of UR-10324, UR-11353, CV-6209 and WEB-2086 markedly inhibited ear oedema induced by the four irritants tested, mimicking the profile obtained with dexamethasone. YM-461 was highly effective only in the dithranol-induced ear oedema, while BN-52021 failed to inhibit ear oedema in all models tested. 3. Leukocyte recruitment into the inflamed ears was prevented by PAF-antagonists, as measured by myeloperoxidase activity in the supernatants of ear homogenates. 4. A relationship between PAF-antagonist and anti-inflammatory activities was found in some cases, but other mechanisms cannot be excluded to explain the topical anti-inflammatory effect of these compounds. 5. Our results suggest that topical formulations containing PAF-antagonists could be useful in the treatment of some inflammatory skin diseases and provide evidence on the involvement of PAF in these inflammatory processes.

Administration, Topical↗

PubMed1990

Comparative study of the effect of CV-6209, a specific PAF-antagonist, on rat paw edema caused by different phlogogen agents.

Comparative effects of CV-6209, a potent and specific platelet activating factor (PAF) antagonist, on PAF-acether-, carrageenin-, histamine-, serotonin-, compound 48/80-, dextran-, zymosan A- and arachidonic acid-induced rat paw edema were investigated. CV-6209 has proven to be effective in PAF-induced edema, but it also showed a significant activity in other models of paw edema, except those induced by zymosan A and arachidonic acid. Other drugs tested, namely indometacin, mepyramine, methysergide and nordihydroguaiaretic acid showed a more selective inhibitory profile. These results suggest an important role of PAF in the inflammatory process caused by intraplantar injection of different phlogogenes in the rat paw.

Animals↗

PubMed1988

The effect of fosfosal and acetylsalicylic acid on leukocyte migration and PGE2 concentration in experimentally induced acute inflammation.

The effect of fosfosal, a non-acetylated salicylic acid derivative, on the content of prostaglandin E2 (PGE2) and the migration of polymorphonuclear leukocytes in inflammatory exudates induced by s.c. implantation of 0.5% carrageenan soaked sponges in rats has been determined. Fosfosal, which does not inhibit PG synthesis in vitro, is capable of reducing, in a dose-dependent manner, the PGE2 content of the exudates, with a maximum reduction of 50-60% at a total dose of 100 mg/kg i.p. Acetylsalicylic acid was slightly more potent (68% reduction, 2 x 50 mg/kg i.p.). Six hours after fosfosal administration, salicylic acid, the principal metabolite of fosfosal, accumulated in the exudates at concentrations of about 100 micrograms/ml. These concentrations were sufficient to inhibit PG synthetase activity in vitro. Neither fosfosal nor acetylsalicyclic acid affected polymorphonuclear leukocyte migration at doses which significantly reduced the concentrations of PGE2. Indomethacin, used as reference, reduced leukocyte migration by 28 and 45% at a dose of 1 and 10 mg/kg i.p. respectively. The results indicate that fosfosal, in spite of its lack of effect on PG biosynthesis in vitro, exerts an effect on the inflammatory locus in vivo which may account, at least in part, for its anti-inflammatory activity. Moreover, our results confirm that the inhibition of PG synthesis and leukocyte migration are mediated by different mechanisms.

Animals↗