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W Peris

Publications and source records attributed to W Peris.

5 recordsLinked to original sources
PubMed1996

Structure-antigastrin activity relationships of new spiroglumide amido acid derivatives.

A series of new spiroglumide amido acid derivatives was synthesized and evaluated for their ability to inhibit the binding of cholecystokinin (CCK) to guinea pig brain cortex (CCKB receptors) and peripheral rat pancreatic acini (CCKA receptors), as well as to inhibit in vitro the gastrin-induced Ca2+ increase in rabbit gastric parietal cells. Appropriate chemical manipulations of the structure of spiroglumide (CR 2194), i.e., (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid, led to potent and selective antagonists of CCKB/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives, as, for example, compound 54 (CR 2622), i.e., (S)-4-[[(R)-4'-[(3,5-dichlorobenzoyl)-amino]-5'-(8- azaspiro[4.5]decan-8-yl)-5'-oxo-pentanoyl]amino]-5- (1-naphthylamino)-5-oxopentanoic acid, exhibit activity 70-170 times greater than that of spiroglumide, depending upon the model used (IC50 = 2 x 10(-8) vs 140 x 10(-8) mol in binding inhibition of [3H]-N-Me-N-Leu-CCK-8 in guinea pig brain cortex and IC50 = 0.7 x 10(-8) vs 122.3 x 10(-8) mol in inhibition of gastrin-induced Ca2+ mobilization in parietal cells of rabbit, respectively). Computer-assisted conformational analysis studies were carried out in order to compare the chemical structure of both the agonist (pentagastrin) and the antagonist (54).

Animals↗
PubMed1992

Antiallergic and cytoprotective activity of new N-phenylbenzamido acid derivatives.

A series of new N-phenylbenzamido acid derivatives was synthesized and evaluated for their ability to inhibit the IgE-mediated passive cutaneous anaphylaxis in the rat (PCA), as well as for their capacity to inhibit gastric mucosal damage induced by the oral administration of absolute alcohol in the rat. Some of these new derivatives exhibit potent antiallergic and cytoprotective activity, 20-80 times higher than that of the reference, disodium cromoglycate (DSCG). Structure-activity relationships are discussed. The antiallergic activity of one of the more potent compounds of this series, i.e. 4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]benzamide (compound 44, CR 2039) was further evaluated in vivo. This compound antagonizes the bronchoconstriction induced by aerosolized ovalbumin in both anesthetized and conscious IgE sensitized guinea pigs with ID50 of 3.7 mg/animal (tracheal insufflation) and 20 mg/kg (im). Further cytoprotective effects were evaluated in gastric ulcer models induced by the acute oral administration of hypertonic sodium chloride solution or by acetic acid and by the subchronic administration of glucose in fasted animals. In the models used experimentally CR 2039 is effective, whereas DSCG seems to be devoid of any protective activity. Such a potent antiallergic and mucosal protectant could provide a new potential agent in the therapy of atopic allergic diseases.

Animals↗
PubMed1992

Structure-antigastrin activity relationships of new (R)-4-benzamido-5-oxopentanoic acid derivatives.

New (R)-4-benzamido-5-oxopentanoic acid derivatives were synthesized by a stereoconservative procedure and evaluated in vitro for their capacity to inhibit the binding of [125I](BH)-CCK-8 to either rat peripheral (CCK-A) or central (CCK-B) CCK receptors, or the binding of [3H]pentagastrin to rabbit gastric glands, as well as to inhibit, in vivo, the acid secretion induced by pentagastrin infusion in the perfused rat stomach. The parent compound of this series (lorglumide) is the first nonpeptidic, potent and selective antagonist of the CCK-A receptor. Chemical manipulations of the structure of lorglumide led to the discovery of selective antagonists of the CCK-B/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives exhibit different affinities with rabbit gastric gland cells and rat cortex membranes, suggesting that the stomach gastrin receptor (arbitrarily termed CCK-B1 receptor) is not as closely related to the CCK central receptor (termed CCK-B2) as previously hypothesized. The antigastric activity of the most potent compound of the series, i.e. (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid (compound 28, CR 2194) was further evaluated in vivo: in the first hour after administration the compound inhibits acid secretion induced by pentagastrin infusion, in both cat and dog (in the cat with gastric fistula and in the dog with Heidenhain pouch), with ID50s (mg/kg) of 15.5 (iv) (cat), 8.7 (IV) (dog) and 24.2 (oral) (Heidenhain dog). The characteristics of CR 2194, that is, the selectivity for the gastrin receptor, the simple nonpeptidic molecular structure, and the activity after oral administration, indicate that this compound is a useful tool in the study of the biological effects of gastrin and a potential agent for diagnostic or therapeutic use.

Animals↗
PubMed1987

Pharmacokinetics and metabolism of [14C]-proglumetacin after oral administration in the rat.

The pharmacokinetics and metabolism of 1H-indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl 2-[4-[3-[[4-(benzoylamino)-5-(dipropylamino)-1, 5-dioxopentyl]oxy]propyl]-1-piperazinyl]ethyl ester (+/-) (proglumetacin, CR 604), 14C-labelled in position C-2 of the indolic moiety, was studied in male and female rats after oral administration. The radioactivity is slowly absorbed from the gastrointestinal tract and reaches the peak in plasma 6 h after administration. Afterwards the radioactivity is eliminated from plasma according to a bi-exponential equation, with an initial elimination rate having a t1/2 of 4.5 h and a terminal elimination rate having a t1/2 of 16 h. The elimination rate is probably dependent on the slow absorption rate (flip-flop system) and on an entero-hepatic recirculation of the radioactivity. The radioactivity is excreted with the feces (60.8%) and with the urines (33.5%). No radioactivity is eliminated with the expired air. About 13% of the fecal radioactivity is represented by proglumetacin. This fraction or radioactivity (ca. 8% of the administered) represents probably the non-absorbed amount of substance. The parent proglumetacin is not found in blood, urine and organs. Conversely several indolic metabolites are found, with a predomination of indometacin. Proglumetacin is therefore a pro-drug of indometacin and of other indolic metabolites, which are responsible for the antiinflammatory activity of proglumetacin. The radioactivity is distributed in all tissues. The maximum radioactivity is found in liver and kidneys, however, always in a smaller concentration than in plasma. No "deep compartment" was found.

Administration, Oral↗