Losartan: An Attempt at Fighting Heart Failure By: Jennifer DeLaet Biochemistry/Molecular Biology...
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Transcript of Losartan: An Attempt at Fighting Heart Failure By: Jennifer DeLaet Biochemistry/Molecular Biology...
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 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?
400,000 new cases a year
Heart Failure causes 38,000 deaths a year
Between 2-3 million Americans suffer from heart failure
When the heart loses its ability to pump enough blood through the body.
Hypertension What is it?
Chronic high blood pressure
May lead to heart attack, stroke, or kidney failure
What is considered high? 140/90mmHg or higher
What is normal? 120/80mmHg
Blood Pressure Systolic Diastolic
Controlling Hypertension
Diet/Exercise
Ca++ Channel Blockers
Beta Blockers
Angiotensin Converting Enzyme
(ACE) Inhibitors
Angiotensin Receptor Blockers
Angiotensin Receptor Blockers
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
The Angiotensin Receptor
The Two Receptor Subtypes
AT1 Receptor, the target of Losartan
AT2 Receptor
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
Summary of the Benefits of Losartan
Decrease in Blood Pressure
Significantly lowers morbidity of stroke-prone rats
Better tolerated then ACE Inhibitors
No increase in Bradykinin
Problems with Losartan
Severe birth defects if taken while pregnant
Concern that the increase in Angiotensin II levels seen during treatment could result inunanticipated results
Some studies show that it took 3-6 weeks for results
Black patients had notably smaller response
Only tested in those 65-75 years old
Future Perspectives
Developing new Angiotensin receptor blockers
Looking at gene and receptor regulation
Looking at finding a renin inhibitor
Products that have high affinity for both receptors
ReferencesNonpeptide 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