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C Scolastico

Publications and source records attributed to C Scolastico.

At least 37 records · Page 2Linked to original sources
PubMed1994

Nonpeptide angiotensin II receptor antagonists. Synthesis, in vitro activity, and molecular modeling studies of N-[(heterobiaryl)methyl] imidazoles.

With the aim of explaining the influence of the structural changes on the biphenylic moiety on the activity, a series of N-[(heterobiaryl)methyl]imidazoles (I), constructed on the model of DuPont compounds by replacing either the central or terminal phenyl ring with a heteroaromatic one, such as furan, thiophene, thiazole, and pyridine, was synthesized. Compared to the reference DuPont compound (EXP-7711), all the heterobiaryl derivatives showed a reduced potency both in receptor binding (rat adrenal capsular membranes) and in the functional assay (angiotensin II-induced contraction of rabbit aorta strips). The lower activity was justified by the extensive molecular modeling studies, which took into consideration the conformational and electrostatic features of several heterobiaryl derivatives. On the basis of the results obtained, it was hypothesized that the central aromatic ring of the biarylic portion works as a spacer, orienting in the right way the terminal phenyl ring, whose electronic distribution is, instead, crucial to its fitting well with a lipophilic pocket at the receptor site.

Adrenal Glands↗
PubMed1994

A 3D QSAR approach to the search for geometrical similarity in a series of nonpeptide angiotensin II receptor antagonists.

A 3D QSAR methodology based on the combined use of conformational analysis and chemometrics was applied to perform a comparative analysis of the 3D conformational features of 13 nonpeptide angiotensin II receptor antagonists showing different levels of binding affinity. Conformational analysis by using a molecular mechanics MM2 method was carried out for each of these structures to obtain conformational minima. These minima were described by ten interatomic distances which define the relative spatial disposition of five significant atoms belonging to relevant functional groups present in all the 13 molecules. The structure-activity relationship between the interatomic distances and the biological activity was then assessed by using chemometric methods (cluster analysis, principal component analysis, classification methods). With our indirect approach based on the search for geometrical similarity it was possible, even though structural information on the receptor active site was lacking, to identify the 3D geometrical requirements for the binding affinity of nonpeptide angiotensin II receptor inhibitors.

Amino Acid Sequence↗
PubMed1992

Pharmacophore identification by molecular modeling and chemometrics: the case of HMG-CoA reductase inhibitors.

A methodology based on molecular modeling and chemometrics is applied to identify the geometrical pharmacophore and the stereoelectronic requirements for the activity in a series of inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme involved in cholesterol biosynthesis. These inhibitors present two common structural features - a 3,5-dihydroxy hepatanoic acid which mimics the active portion of the natural substrate HMG-CoA and a lipophilic region which carries both polar and bulky groups. A total of 432 minimum energy conformations of 11 homologous compounds showing different levels of biological activity are calculated by the molecular mechanics MM2 method. Five atoms are selected as representatives of the relevant fragments of these compounds and three interatomic distances, selected among 10 by means of a Principal Component Analysis (PCA), are used to describe the three-dimensional disposition of these atoms. A cluster analysis procedure, performed on the whole set of conformations described by these three distances, allows the selection of one cluster whose centroid represents a geometrical model for the HMG-CoA reductase pharmacophore and the conformations included are candidates as binding conformations. To obtain a refinement of the geometrical model and to have a better insight into the requirements for the activity of these inhibitors, the Molecular Electrostatic Potential (MEP) distributions are determined by the MNDO semiempirical method.

Electrochemistry↗
PubMed1992

Prolonged retention of doubly labeled phosphatidylcholine in human plasma and erythrocytes after oral administration.

The plasma kinetics of a preparation of dilinoleoyl phosphatidylcholine (DLPC) specifically labeled with 3H in the choline moiety and with 14C in the 2-fatty acid (FA) were evaluated in six healthy volunteers after oral administration. Retention of both isotopes in plasma exceeded expectations, with a half-life in the elimination phase of 172.2 h for 3H and 69.7 h for 14C. Up to 60 d after administration, there were still significant levels of radioactivity present in plasma. The relative stability of the [14C]FA label was demonstrated by the retention for more than 12 h of an isotope ratio close to that of the compound administered. The 14C label of DLPC remained in position-2, as assessed by cleavage of plasma phospholipids with phospholipase A2. The [3H]choline label showed an early incorporation into high density lipoproteins and subsequently into low density lipoproteins (LDL); conversely, the 14C radioactivity was rapidly incorporated into triacylglycerols that were mainly associated with very low density lipoproteins. Radioactivity measurements revealed that both isotopes remained the longest time in LDL. In red blood cell (RBC) lipids, [3H]choline radioactivity accumulated over time, with a plateau after 48 h, whereas FA radioactivity accumulated more rapidly and was followed by a progressive decay. Analysis of the isotope ratio in these cells suggested an early incorporation of lyso products followed by rapid transfer of FA from plasma. The RBC maintained considerable radioactivity for a prolonged time, thus acting as a possible reservoir for the DLPC administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Structure-activity relationship of Ca2+ channel blockers: a study using conformational analysis and chemometric methods.

A structure-activity relationship study has been done on 8 compounds with the activity known as 'Ca2+ channel blockers'. Conformational analysis was carried out using a molecular mechanics method. The 3D-QSAR approach was used and the most polar functional groups present in all the molecules were considered. Eight interatomic distances are necessary to define the relative spatial disposition of these relevant molecular fragments. The structure-activity relationship between interatomic distances and biological activity was performed using statistic and chemometric methods. In particular, with Principal Component Analysis, it was possible to reduce the number of interatomic distances: only six of the eight distances are sufficient to describe the system in a useful way. A classification method was iteratively used to select the most probable conformations linked to the biological activity and to build a model able to classify conformations according to their biological behaviour. Cluster analysis on the active selected conformations subsequently allowed the identification of two different geometrical patterns for the active compounds. Finally the validity of the model was verified by correctly predicting the activity of other molecules not used in the construction of the model but possessing known activity.

Calcium Channel Blockers↗
PubMed1986

Novel derivatives of 3 alpha,7 alpha-dihydroxy-5 beta-cholan-24-oic acid (chenodeoxycholic acid) and 3 alpha,7 beta-dihydroxy-5 beta-cholan-24-oic acid (ursodeoxycholic acid).

Several 7-acyl cheno- and ursodeoxycholic acids were obtained in good yields starting from the corresponding cheno- and ursodeoxycholic acids, by a diacylation-selective hydrolysis procedure. A superior method for the synthesis of the 7-oleyl derivatives, by a selective acylation procedure, is also presented.

Chemical Phenomena↗
PubMed1984

Synthesis of 2-carboxy-11 beta, 17 beta-dihydroxy-17-methyl-1, 4-androstadien-3-one and related compounds.

A series of 2-carboxy-1, 4-androstadien-3-one derivatives and their alkyl esters, were prepared by high-yield syntheses. The compounds were structurally identified by physical methods. All these steroids are characterized by a marked antiglucocorticoid activity that proved long-acting in the case of the ester derivatives. 2-Carboxy-11 beta, 17 beta-dihydroxy-17-methyl-1, 4-androstadien-3-one or roxibolone, and its n-decylester or decylroxibolone, are the most promising derivatives in consideration of their pharmacological properties.

Androstadienes↗
PubMed1984

Novel pyrimidine and 1,3,5-triazine hypolipidemic agents.

New compounds were synthesized by changing the substituents of a trisubstituted pyrimidine, i.e., [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio] acetic acid, a potent hypolipidemic agent, impaired, however, by a marked hepatomegaly-inducing effect. The structural variations led to the subsidence (14b, i.e., 4-chloro-2-(dimethylamino)-6-[(2,3-dimethylphenyl)amino]pyrimidine) or to the reduction (18b, [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]amino] acetic acid) of said untoward effect but still maintained the hypolipidemic effect that, although markedly decreased, still proves significant for serum cholesterol and triglycerides (18b) or for serum triglycerides only (14b).

Animals↗
PubMed1978

Pharmacological profile of BR-931, a new hypolipidemic agent that increases high-density lipoproteins.

BR-931 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio-(N-beta-hydroxyethyl)-acetamide], a new hypolipidemic agent of low toxicity, was evaluated in several tests of lipolysis and hyperlipidemia in rats, and in the cholesterol-induced atherosclerosis in rabbits. Significant hypolipidemic activity was observed in rats with doses of the agent at 12.5--50 mg/kg. In the Triton-induced hyperlipidemia, 50 mg BR-931 per kg was equieffective as 200 mg of clofibrate (CPIB) per kg. In contrast with CPIB, BR-931 exerted a powerful antilipolytic activity against epinephrine, ACTH, nicotine and cold exposure. BR-931 was particularly effective in diet-induced hyperlipidemias. Ethanol lipemia was totally prevented by the agent at 100 mg/kg. With Nath's diet, doses as low as 25 mg/kg significantly reduced hypercholesterolemia and hypertriglyceridemia. In these last two tests, the distribution of lipoprotein cholesterol was also determined. CPIB did not affect HDL cholesterol levels that had been decreased by the diets; in contrast, BR-931, already at doses of 50 mg/kg, brought the HDL/total cholesterol ratio back toward normal. A significant HDL cholesterol increase, together with some reduction of atheromatosis, was also observed in cholesterol-fed rabbits. BR-931, a potent inducer of liver peroxisones and of mitochondrial carmitine acetyltransferase, appears to be a hypolipidemic agent of high efficacy and low toxicity for the clinical treatment of hyperlipidemias and atherosclerosis.

Acetamides↗
PubMedDate not supplied

Long-term epidemiological survey of hepatitis B virus infection in a hyperendemic area (Afragola, southern Italy): results of a pilot vaccination project.

In 1983, a pilot project of universal hepatitis B vaccination was introduced in a hyperendemic area in southern Italy (Afragola) and is ongoing to date. In this area before the start of vaccination, we found significant evidence of HBV endemicity: the acute viral hepatitis B incidence in the general population averaged 63/100,000; the HBsAg and anti-HBc prevalence rates were 13.4% and 66.9%, respectively; there was involvement of hepatitis B virus (HBV) in 48.1% of chronic liver pathologies (46.3%) in chronic viral hepatitis, 49.5% in cirrhosis and 71.7% in hepatocellular carcinoma cases). We studied the acute viral hepatitis incidence during the vaccination period from 1983 to 1997 and compared the HBsAg and anti-HBc prevalences in 1978 to those in 1997, after 15 years of vaccination. The HBV-related chronic pathology prevalence was also studied. We found a remarkable drop in the acute viral hepatitis incidence, from an average annually of 63/100,000 in the five years before vaccination to 3/100,000 in the last five years of vaccination. In addition, the HBsAg carrier prevalence in the general population decreased from 13.4% in 1978 to 3.7% in 1997. The percentage dropped in children and adolescents from 6.8% to 0.7%, in young people from 10.2% to 1.1% and in adults from 15.8% to 4.0%. The anti-HBc carrier prevalence, found to be 66.9% in 1978, was 34.2% in 1997. Finally, we found a much less significant involvement of HBV in chronic liver pathologies; in fact, it was present in only 18.2% of cases in 1997 and in 48.2% in 1982. In the light of the data, we can assert that universal hepatitis B vaccination has had a substantial effect on HBV endemicity in the Afragola area. We believe that the reduction found in the incidence of acute viral hepatitis B and HBV-related chronic liver pathologies is connected to the decrease in HBV carriers in the area, which therefore reduces the risk of contagion for the unvaccinated.

Adolescent↗