1. Losartan: An Attempt at Fighting Heart Failure By: Jennifer DeLaet Biochemistry/Molecular Biology Seminar University of Wisconsin-Eau Claire March 29, 1999

2. Topics of Discussion n Heart Failure n Hypertension n The Angiotensin system and how it causes hypertension n Stopping angiotensin, stopping heart failure n Losartan, an angiotensin receptor antagonist n Benefits and problems of Losartan n References

3. Heart Failure n What is heart failure? n 400,000 new cases a year n Heart Failure causes 38,000 deaths a year n Between 2-3 million Americans suffer from heart failure When the heart loses its ability to pump enough blood through the body.

4. Causes of Heart Failure n Heart Disease n Aging n Smoking n High cholesterol levels n Diabetes n Hypertension

5. Hypertension n What is it? Chronic high blood pressure n May lead to heart attack, stroke, or kidney failure n What is considered high? 140/90mmHg or higher n What is normal? 120/80mmHg n Blood Pressure Systolic Diastolic

6. Controlling Hypertension n Diet/Exercise n Ca++ Channel Blockers n Beta Blockers n Angiotensin Converting Enzyme (ACE) Inhibitors n Angiotensin Receptor Blockers

7. Renin-Angiotensin System Taken from Wexler, et al.

8. Angiotensin Receptor Blockers n The next idea to target Angiotensin II -Peptide Antagonists -Nonpeptide Antagonists. Poor oral bioavailability. Short duration of action. Significant agonists properties. Takeda Chemical Industries. Du Pont

9. The Angiotensin Receptor n The Two Receptor Subtypes n AT1 Receptor, the target of Losartan n AT2 Receptor

10. The AT1 Receptor - A 7-alpha helix receptor which is a G-protein coupled -Taken from Wexler, et al

11. The Invention of Losartan Taken from Wexler, et al.

12. Taken from www.pharmazie.uni-marburg.de/Neue.Arzneimittel/Losartan.html

13. The use of Ang II to design Losartan n Ang II’s C-terminal segment n Side chain arrangement triggers receptor action n Ang II’s Phe-COOH group

14. How Losartan Works n Competitive inhibitor

16. How Losartan Works Competitive inhibitor Metabolite, EXP3174

17. Summary of the Benefits of Losartan n Decrease in Blood Pressure Significantly lowers morbidity of stroke-prone rats Better tolerated then ACE Inhibitors No increase in Bradykinin

18. Problems with Losartan n Severe birth defects if taken while pregnant n Concern that the increase in Angiotensin II levels seen during treatment could result in unanticipated results n Some studies show that it took 3-6 weeks for results n Black patients had notably smaller response n Only tested in those 65-75 years old

19. Future Perspectives n Developing new Angiotensin receptor blockers n Looking at gene and receptor regulation n Looking at finding a renin inhibitor n Products that have high affinity for both receptors

20. References Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy. Wexler, R.R., et al. J. Med. Chem. 1996 Feb 2;39 Synthesis and Structure-Activity Relationship of a New Series of Potent AT1 Selective Angiotensin II Receptor Antagonists: 5-(Biphenyl-4-ylmethyl) pyruzoles. Almansa, C., et al. J. Med. Chem. 1997; 40, 547-58. Targeting the Receptor-Gq Interface to Inhibit in Vivo Pressure Overload Myocardial Hypertrophy. Akhter, S.A., et al. Scince 280(5363): 574 Design, Synthesis, and Biological Activities of Four Angiotensin II Receptor Ligands with Gamma turn Mimetics Replacing Amino Acid Residues 3-5. Schmidt, B., et al. Ept.of Organic Pharmaceutical Chem. And Medical and Physiological Chem., Uppsala University. 1996 The Active State of the AT1 Angiotensin Receptor is Generated by Angiotensin II Induction. Noda, K., et al. Dept. of Molecular Cardiology, The Cleveland Clinic Foundation, 1996.

21. References Cont. Nonpeptide Antiotensin II Receptor Antagonists: Synthesis, Biological Activities, and Structure-Activity Relationships of Imidazole-5-carboxyalkyl Acid Bearing Alkyl, Alkenyl, and Hydroxyalkyl Substituents at the 4-Position and Their Related Compounds. Hiroaki, Y., et al. Research Institute, Sankyo Company, Ltd. 1995 Losartan-induced Angiodema. Medical Sciences Bullitin 1996; 18(9):6 Blood Pressure Effects of the Angiotensin II Receptor Blocker, Losartan. Weber, M.A., et al. Arch Intern Med. 1995 Feb 27;155(4) 405-11 http://www.mayohealth.org/mayo/9708/htm/hyperten.htm http://www.jhbmc.jhu,edu/cardiology/rehab/hypertension.html

22. Cont. References http://www.pharmazie.uni.marburg.de/Neue-Arznoimittel/ Losartan.html http://www.pharmacy.ab.umd.edu/~umdi/losarrev.htm

23. GO DUKE