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SYNTJitESIS OF NEW NONPEPTIJIE ANGIOTENSIN Jl RECEPTOR ANTAGONISTS A. Sscchi. F. Arena, E. Abignente, S. Laneri, M. Gallitelli Dipartimento di Chimica Farmaceutica e Tossicologica, Via D. Montesano, 49, 8013 1 Napoli, Italia.

The linear octapeptide angiotensin II is a potent vasoconstrictor produced by the renin-angiotensin cascade which regulates blood pressure homeostasis, fluid volume and electrolyte balance in msmrnals. Angiotensin II (AH) interacts with specific cellular receptors causing vasoconstriction, aldosterone secretion, renal sodium retention and other biological etfects. Pharmacological blockade of the renin-angiotensin system with inhibitors of angiotensin converting enzyme (ACE) such as captopril and enalapril efTectively lowers AH levels and is estabilished therapy for the treatment of essential hypertension and congestive heart failure. Recently, non peptidic and orally active AII receptor antagonists have emerged as alternative and potentially superior agents for lowering blood pressure in hypertensive patients.

Our research involves the synthesis of a new class of imidazo[l,2-alpyridine antagonists:

These compounds displayed potent AI1 antagonists activity: in fact they showed SO-90% inhibition of blood pressure response to AI1 adminisatration in conscious normotensive rats.

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SIMULTANEOUS DETERMINATION OF MIXTURES OF DRUGS CANDIDATES BY HPLC/MS/MS AS AN “IN V/W PHARMACOKINETIC SCREENING PROCEDURES M. Scandola, S. Braggio, P. Rossato and M. Pellegatti Glaxo Wellcome S.p.A., Drug Metabolism and Pharmacokinetics, Via A. Fleming, 4, 37135 Verona, Italy

HPLC combined with tandem mass spectrometry (HPLCMkMS) has become a fundamental tool in the pharmaceutical industry with particular influence for both Drug Discovery and Drug Development programs. In the current environment in the Pharmaceutical Industry, Chemistry Departments have increased their output of New Chemical Entities (NCE) through the use of such techniques as combinatorial chemistry. Biological screening techniques are used to identify in-vitro “hits” which are progressed further into in-tiw models of activity. At this stage it is important to optimize the pharmacokinetic (PK) and metabolism of lead compounds. The optimization of phannacokinetics relies on performing in-viw PK studies in animals, generating numerous samples. LC/MS/MS together with new approaches in drug administration and analysis, enables a remarkable increase in producttvity. This presentation describes how LCMSiMS has enabled a very high speed method development and assay and has allowed large number of assays to be performed.

ARTIFICIAL NEURAL NETWORKS AS PREDICTIVE TOOL IN QSAR-STUDIES OF PROPAFENONF-TYPE MODULATORS OF MULTIDRUG RESISTANCE C. Tmej, G. Ecker, P. Chiba, K.-J. Schaper, W. Fleischacker Institute of Pharmaceutical Chemistry, University of Vienna, Althanstr. 14, A- 1090 Wien, Austria

Following our ongoing studies for development of highly active inhibitors of the multidrug transporter P-glycoprotein (PGP) we performed a combined Hans&/Free-Wilson analysis on 48 propafenone-type modulators of multidrug resistance (MDR). The data set was analyzed using both multiple linear regression (MLR) analysis and an artificial neural network (ANN) configured as fully connected, feed forward three layer perceptron with backpropagation algorithm. The predictive abilities of both methods were compared using the Qr-values of both leave one out and leave eight out cross validation procedures. Leave one out cross validation gave nearby identical results with Q’-values in the range of 0.66 (MLR) and 0.56 (ANN), respectively. Nevertheless, in the leave eight out cross validation procedure, the ANN showed remarkably higher predictive abilities (Q’ = 0.70 (ANN) vs. 0.44 (MLR). T-test (MLR) and a genetic input selection algorithm (ANN) were used to identify those x- descriptors which influence with highest significance MDR- modulating activity of the compounds. Interestingly, both methods led to models with nearby identical predictiveness, although despite molar refraction and lipophilicity several different x-descriptors (mainly indicator variables from the Free- Wilson data matrix) remained in the final data set.

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Hydropatbicity of allosteric modulators ofthe MZ receptors G&ml& A. Pedra&, A.M. Villa’, L. Villa’, U. Holzgrabe’,

* Pharmazeutiscbes lnstitut, Univarsititt Bonn. g Istituto di Chimica Fannaceatica, Univarsita di Milaao

The hydropatbicity of a series of compounds active as allostsric modulators at the Mr muscarinic receptors was studied. The compounds were submitted to a detailed ccnformational search in vacua with a MonteCarlo method, followed by a Molecular Dynamics simulation The lowest energy conformation was inserted in ao appropriate size watsr cluster and the system was again subjected to a detailed Molecular Dynamics procedure. The hydrcpathicity profile was then calculate and projected on the molecular surface. The results were compared with the experimental lipopbilicity v&X. An analysis of the mlaticnshipr bstween confomrational and local hydropathicity properties was also pmfmltled.