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

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Topics of Discussion

• 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

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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

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Causes of Heart Failure

• Heart Disease
• Aging
• Smoking
• High cholesterol levels
• Diabetes
• Hypertension

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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

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Controlling Hypertension

• Diet/Exercise
• Ca Channel Blockers
• Beta Blockers
• Angiotensin Converting Enzyme (ACE) Inhibitors
• Angiotensin Receptor Blockers

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Renin-Angiotensin System

• Taken from Wexler, et al.

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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
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The Angiotensin Receptor

• The Two Receptor Subtypes

• AT1 Receptor, the target of Losartan

• AT2 Receptor

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The AT1 Receptor

• - A 7-alpha helix receptor which is a G-protein
  coupled

-Taken from Wexler, et al
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The Invention of Losartan
Taken from Wexler,
et al.
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Taken from www.pharmazie.uni-marburg.de/Neue.Arzne
imittel/Losartan.html
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The use of Ang II to design Losartan

• Ang IIs C-terminal segment

• Side chain arrangement triggers receptor action

• Ang IIs Phe-COOH group

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How Losartan Works

• Competitive inhibitor

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How Losartan Works

• Competitive inhibitor

• Metabolite, EXP3174

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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

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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

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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

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References

• Nonpeptide Angiotensin II Receptor Antagonists
  The Next Generation in
• Antihypertensive Therapy. Wexler, R.R., et
  al. J. Med. Chem. 1996 Feb 239
• 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.

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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 27155(4)
• 405-11
• http//www.mayohealth.org/mayo/9708/htm/hyperten.h
  tm
• http//www.jhbmc.jhu,edu/cardiology/rehab/hyperten
  sion.html

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Cont. References

• http//www.pharmazie.uni.marburg.de/Neue-Arznoimit
  tel/
• Losartan.html
• http//www.pharmacy.ab.umd.edu/umdi/losarrev.htm

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GO DUKE