1. Losartan: An Attempt at Fighting Heart Failure
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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 Heart Failure Hypertension
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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

3. Heart Failure What is heart failure?
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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

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

5. Hypertension What is it? Chronic high blood pressure Blood Pressure
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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

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

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

8. Angiotensin Receptor Blockers
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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

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

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

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

12. 11/7/2018
Taken from

13. The use of Ang II to design Losartan
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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

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How Losartan Works
Competitive inhibitor

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How Losartan Works
Competitive inhibitor
Metabolite, EXP3174

17. Summary of the Benefits of Losartan
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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

18. Problems with Losartan
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Problems with Losartan
Severe birth defects if taken while pregnant
Only tested in those 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

19. Developing new Angiotensin receptor blockers
Future Perspectives
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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

20. References
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Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in
Antihypertensive Therapy. Wexler, R.R., et al. J. Med. Chem 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,
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.
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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 Feb 27;155(4)
405-11

22. Cont. References
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Losartan.html

23. 11/7/2018
GO DUKE