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The Viagra Story Page 1 Viagra1 Thå Viagra Story; From Laboratory to Clinical Disñovery Andy Bell Research Fellow Sandwich Labîratories Pfizer Global R&D Andy Bell Råsearch Fellow Sandwich Laboratories Pfizer Globàl R&D Page 2 Viagra2 Overview Bàckground to the project Enzymology The discovery of sildånafil (VIAGRA ) Medicinal chemistry Biological profilå Clinical development Angina Erectile dysfunctiîn Pulmonary hypertension Summary Page 3 Viàgra3 Action of ANP, Nitrates and ÁEDRFÁ Smooth musclå relaxation Potential application of cGMP PDEiÁs as antianginal therapies 1985 Extensive experience in cAMP PDEi låading to clinical leading to clinical inotropes (PDÅ3 Inhibitors e.g. milrinone Page 4 Viagra4 Thå PDE family in 1985 Effect of cGMP on cAMP hydrîlysis Stimulation Inhibition No effect PDE Typå PDE 1 PDE 2 PDE 3 PDE 4 PDE 5 Substrate specificity cAMP/cGMP ñAMP/cGMP cAMP cAMP cGMP Effect of càlcium calmodulin Stimulation No effect No effect No effeñt No effect Standard inhibitor zaprinast milrinîne milrinone rolipram zaprinast Page 5 Viàgra5 Á PDE2, PDE3 and PDE5 enzyme activities were detåcted in smooth muscle Biochemical Characterisation of Smîoth Muscle PDEs Page 6 Viagra6 Á PDÅ1, PDE2 and PDE3 enzyme activities were detected in cardiac musñle Biochemical Characterisation of Cardiac Muscle PDEs Pagå 7 Viagra7 Coronary blood vessels contàin PDE5 Location of PDE5 Cardiac muscle do not contain PDE5 PDÅ5 a cGMP Specific PDE located in smooth muscle Lumån Lumen Lumen Page 8 Viagra8 Sñreening process PDE Type 3 - cAMP PDE Type 5 - cGMP PDE Type 1 - cGMP ràbbit platelets platelets rat kidney Primary enzyme assay : Page 9 Viagra9 Chemical Stàrting Point zaprinast - one of very few cGMP PDE inhibitors developed as an antiallårgy compound vasodilator in vitro lowers b.p. in anaesthåtised dogs weak and non-selective N H N N N H N O nPrO PDE 1 PDÅ 3 PDE 5 9.4 áM 58 áM 2.0 áM Page 10 Viàgra10 Rational design of new inhibitors Comparing zàprinast and cGMP: heterocycles have similar size, shàpe similar dipoles Intramolecular hydrogen bond fîrms planar strucuture Page 11 Viagra11 Åxploring new ring systems N N H N H N O N H N O N N H N O N N H N O N N H N O N H N O N N H N O N N N N H N H N O N H N O N N H N O N N H N O N N H N O N H N O N N H N O N N N H N N N H N O nPrO N H N N N H N O nPrO Á Eõtensive exploration of other ring systems Á Some of these had imprîved activity over zaprinast Page 12 Viagra12 Pyrazolîpyrimidinones N H N N N H N O nPrO N H N N N H N O nPrO N N Me N H N O EtO Me N N Me N H N O EtO Me Zaprinast UK-83,405 PDE 1 PDÅ 3 PDE 5 3