Project: Preclinical Evaluation of Elsartan in Preparation of NDA for Clinical Phase I and II Studies.

ELDRUG SA, a newly established High Tech Company in Drug Discovery and Design in Greece located in Patras. It owns the rights of Elsartan and related compounds and plans to proceed towards clinical investigation for transdermal delivery in treating Hypertension. _x000D_Elsartan is a specific and selective Angiotensin II Receptor Antagonist discovered in the Laboratories of ELDRUG SA, with very good indication for treating hypertension. Its potency in a number of Experimental Protocols and the use of several delivery methods has been demonstrated. Elsartan, has an extremely cost effective method of synthesis of the compound by novel strategic synthetic procedures we have developed in our Chemical Laboratories. It exhibits a number of properties which render this compound a potential drug in treating Hypertension and Cardiovascular diseases. Chemical transformation to lipophilic or hydrophilic potent forms would allow a patch delivery which is a demand in modern Medicine especially for aged and elderly people. In particular, Elsartan, in comparison with Losartan the first drug in the Sartan series, shows an equipotent binding to Angiotensin II Receptors and the same or better potency in a series of bioassays (Calcium blocker, anesthetized and non anesthetized rabbits, safety and toxicity). It has the advantage of highly cost effective synthesis as well as lipophilic properties which enable transdermal delivery. This project aims to accelerate development towards Clinical Phase I and II studies by performing preclinical toxicity, pharmacokinetics and safety trials in experimental models to be carried out by Cardiomed CRO SRL Company._x000D__x000D_In particular, ELDRUG SA will scale up synthesis of Elsartan and provide information regarding the synthetic steps involved in manufacturing the compound. Analytical techniques have been developed to monitor the active compound and its metabolites in body fluids. In addition the formulation of the active ingredient will be investigated for oral or transdermal delivery. Both drug product and active ingredient will be characterized as to strength, purity and stability. ELDRUG SA also will perform detailed pharmacology and drug distribution studies:_x000D_a) Dose response of pharmacologic effects and mechanism of action._x000D_b) The absorption, distribution, metabolism and excretion of the drug in one or more animal species._x000D__x000D_The participant company will complete toxicology studies in two animal species including acute toxicity studies and long term toxicity and histological evaluations of the treated animals. _x000D__x000D_This project is the result of a long R&D journey initiated since 1982 which included advanced peptide and organic chemistry and in particular conformational work which provided a Synthetic Molecular Model. This model is considered the closest to the Angiotensin Receptor Model and appeared in a number of highly regarded publications (J. Biol. Chem., 269, 5303, 1994). Elsartan is protected by Patent Applications submitted to Greek Patent Office (GPO), United Kingdom Patent Office (UK PO), European Patent Office (EPO) and PCT._x000D__x000D_Biological Evaluations of Elsartan in a number of assays, justify further studies by carrying out preclinical acute and chronic toxicology and histological evaluations for development as potential anti hypertensive drug:_x000D_1. Affinity _x000D_2. Potency _x000D_3. Early Toxicity_x000D_4. Trasdermal Delivery _x000D__x000D_For the study of the antihypertensive action of the synthesized molecule ELSARTAN , two experimental models are used. One of the experimental models is referred to non anesthetized rabbits while the other is referred to anesthetized rabbits. As a report of the measures we use Losartan. We have seen that we have downfall of the mean pressure in the same levels as the losartan bring about._x000D__x000D_Transdermal drug delivery offers certain advantage compared to systematic due to avoidance of first pass effect, less side effects and better patient compliance. Permeation experiments through human skin showed that BV6 molecule overcomes the skin barrier relatively easily. _x000D_Future goal of this study is to increase the permeability of the molecule using chemical enhancers, such as propylene glycol (PG), terpenes (cineole) which can also be used in transdermal patches. Another tactic would be to use separated human epidermis as a skin model. _x000D__x000D_The Radioligand Binding Assay was used to determine the IC50 and Ki of the test substance. Competitive binding experiments revealed that ELSARTAN produced a concentration-dependent and complete inhibition of the [125I]-Sar1-Ile8-angiotensin II action._x000D__x000D_Also, based on guideline 423 that was adopted by OECD 2001 we defined the lethal dose of ELSARTAN in two species of rodents, Balb-C mice and Wistar rats. The lethal dose ip for ELSARTAN is >300 mg/kg b.w.. The histopathology estimation will be performed eminently._x000D__x000D_We consider these first results very encouraging, and bioavailability, pharmacokinetics and advanced toxicity assays should also take place.

Acronym ELSARTAN (Reference Number: 4307)
Duration 01/09/2008 - 01/01/2011
Project Topic Elsartan, an Angiotensin II Receptor Antagonist, discovered in our Laboratories of ELDRUG SA, is a potential drug for treating Hypertension and Cardiovascular Diseases with many advantages compared to other Sartans as a highly cost effective and transdermal delivery agent due to its lipophilicity.
Network Eurostars
Call Eurostars Cut-Off 1

Project partner

Number Name Role Country
2 HELLAS ELDRUG Coordinator Greece
2 Cardiomed CRO SRL Partner Romania