Transcript Losartan: An Attempt at Fighting Heart Failure

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

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
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?
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






Heart Disease
Aging
Smoking
High cholesterol levels
Diabetes
Hypertension
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

Diet/Exercise

Ca++ Channel Blockers

Beta Blockers

Angiotensin Converting Enzyme
(ACE) Inhibitors

Angiotensin Receptor Blockers
Renin-Angiotensin System
Taken from Wexler, et al.
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

The Two Receptor Subtypes

AT1 Receptor, the target of Losartan

AT2 Receptor
The AT1 Receptor
- A 7-alpha helix receptor which is a G-protein coupled
-Taken from Wexler, et al
The Invention of Losartan
Taken from Wexler, et al.
Taken from www.pharmazie.uni-marburg.de/Neue.Arzneimittel/Losartan.html
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
How Losartan Works

Competitive inhibitor
How Losartan Works

Competitive inhibitor

Metabolite, EXP3174
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

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

Future Perspectives

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
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.
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
http://www.pharmazie.uni.marburg.de/Neue-Arznoimittel/
Losartan.html
http://www.pharmacy.ab.umd.edu/~umdi/losarrev.htm
GO DUKE