Losartan: An Attempt at Fighting Heart Failure 11/28/2018 Losartan: An Attempt at Fighting Heart Failure By: Jennifer DeLaet Biochemistry/Molecular Biology Seminar University of Wisconsin-Eau Claire March 29, 1999

Topics of Discussion Heart Failure Hypertension 11/28/2018 Heart Failure Hypertension The Angiotensin system and how it causes hypertension Stopping angiotensin, stopping heart failure Losartan, an angiotensin receptor antagonist Benefits and problems of Losartan References

Heart Failure What is heart failure? 11/28/2018 Heart Failure What is heart failure? When the heart loses its ability to pump enough blood through the body. Between 2-3 million Americans suffer from heart failure Heart Failure causes 38,000 deaths a year 400,000 new cases a year

Causes of Heart Failure 11/28/2018 Causes of Heart Failure Heart Disease Aging Smoking High cholesterol levels Diabetes Hypertension

Hypertension What is it? Chronic high blood pressure Blood Pressure 11/28/2018 Hypertension What is it? Chronic high blood pressure Blood Pressure Systolic Diastolic What is normal? 120/80mmHg What is considered high? 140/90mmHg or higher May lead to heart attack, stroke, or kidney failure

Controlling Hypertension 11/28/2018 Controlling Hypertension Diet/Exercise Ca++ Channel Blockers Beta Blockers Angiotensin Converting Enzyme (ACE) Inhibitors Angiotensin Receptor Blockers

Renin-Angiotensin System 11/28/2018 Taken from Wexler, et al.

Angiotensin Receptor Blockers 11/28/2018 Angiotensin Receptor Blockers The next idea to target Angiotensin II -Peptide Antagonists . Poor oral bioavailability . Short duration of action . Significant agonists properties -Nonpeptide Antagonists . Takeda Chemical Industries . Du Pont

The Angiotensin Receptor 11/28/2018 The Angiotensin Receptor The Two Receptor Subtypes AT1 Receptor, the target of Losartan AT2 Receptor

- A 7-alpha helix receptor which is a G-protein coupled The AT1 Receptor 11/28/2018 - A 7-alpha helix receptor which is a G-protein coupled -Taken from Wexler, et al

The Invention of Losartan 11/28/2018 The Invention of Losartan Taken from Wexler, et al.

11/28/2018 Taken from www.pharmazie.uni-marburg.de/Neue.Arzneimittel/Losartan.html

The use of Ang II to design Losartan 11/28/2018 The use of Ang II to design Losartan Ang II’s C-terminal segment Side chain arrangement triggers receptor action Ang II’s Phe-COOH group

11/28/2018 How Losartan Works Competitive inhibitor

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How Losartan Works Competitive inhibitor Metabolite, EXP3174 11/28/2018 How Losartan Works Competitive inhibitor Metabolite, EXP3174

Summary of the Benefits of Losartan 11/28/2018 Summary of the Benefits of Losartan Decrease in Blood Pressure No increase in Bradykinin Better tolerated then ACE Inhibitors Significantly lowers morbidity of stroke-prone rats

Problems with Losartan 11/28/2018 Problems with Losartan Severe birth defects if taken while pregnant Only tested in those 65-75 years old Black patients had notably smaller response Some studies show that it took 3-6 weeks for results Concern that the increase in Angiotensin II levels seen during treatment could result in unanticipated results

Developing new Angiotensin receptor blockers Future Perspectives 11/28/2018 Developing new Angiotensin receptor blockers Products that have high affinity for both receptors Looking at finding a renin inhibitor Looking at gene and receptor regulation

References 11/28/2018 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.

References Cont. 11/28/2018 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

Cont. References 11/28/2018 http://www.pharmazie.uni.marburg.de/Neue-Arznoimittel/ Losartan.html http://www.pharmacy.ab.umd.edu/~umdi/losarrev.htm

11/28/2018 GO DUKE