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.

Causes of Heart Failure

Heart Disease Aging Smoking High cholesterol levels Diabetes Hypertension

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

Renin-Angiotensin System

Taken from Wexler, et al.

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 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

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

GO DUKE