Direct renin inhibitors as antihypertensive drugs
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www.pharmaxchange.info. DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS. DATE – OCTOBER 23 rd , 2009 PRESENTED BY – AKUL MEHTA VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF PHARMACY DEPARTMENT OF MEDICINAL CHEMISTRY. www.pharmaxchange.info. WHAT IS HYPERTENSION?.

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DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS

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DIRECT RENIN INHIBITORS AS ANTIHYPERTENSIVE DRUGS

DATE – OCTOBER 23rd, 2009

PRESENTED BY – AKUL MEHTA

VIRGINIA COMMONWEALTH UNIVERSITYSCHOOL OF PHARMACY

DEPARTMENT OF MEDICINAL CHEMISTRY


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WHAT IS HYPERTENSION?

  • Normal Blood Pressure = 120/80

    • Systolic = 90 – 119 mm Hg

    • Diastolic = 60 – 79 mm Hg

  • Hypertension = High Blood Pressure

  • Known risk factor of several Cardiovascular Disorders

Chobanian, A. V. et al.Hypertension2003,42, 1206-1252


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RENIN ANGIOTENSIN SYSTEM

  • AngI = Angiotensin I

  • ACE = Angiotensin converting enzyme

  • AngII = Angiotensin II

Image adapted from - Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.


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CURRENT DRUGS TARGETING THE RENIN-ANGIOTENSIN SYSTEM FOR HYPERTENSION

IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE

DRUG?


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NEED FOR ANOTHER ANTIHYPERTENSIVE

  • Hypertension needs modulation

Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.

Image from - http://blog.wineenthusiast.com/wp-content/uploads/2008/12/balance.jpg


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NEED FOR ANOTHER ANTIHYPERTENSIVE

  • Limitations of current drugs targeting the system

Li, Y. C. Curr. Opin. Invest. Drugs 2007, 8, 750-757.


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NEED FOR ANOTHER ANTIHYPERTENSIVE

  • Hypertension  1° risk factor in cardiovascular diseases

  • Worldwide prevalance of ≈ 1 billion people (almost 1/6th of the human population)

  • United States of America > 60 million people

  • < 30% of patients achieve treatment goals

IS THERE REALLY A NEED FOR ANOTHER ANTIHYPERTENSIVE

DRUG?

YES THERE IS DEFINITELY A NEED

Yokokawa, F. et al. Expert Opin. Ther. Patents 2008,18(6), 581-602.


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CURRENT INTEREST IN INHIBITION OF RENIN ANGIOTENSIN SYSTEM

Yokokawa, F. et al.Expert Opin. Ther. Patents 2008,18(6), 581-602.


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INTRODUCING RENIN

  • History

  • Structure

  • Function

  • Mechanism

PDB ID – 2v0z


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RENIN - HISTORY

  • 1898- Tigerstedt and Bergman

    • Kidney extracts produce pressor effects- coined the term ‘renin’

Phillips, M. I. News Physiol. Sci. 1999,14, 271-274


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RENIN - HISTORY

  • 1934- Harry Goldblatt

    • Induced experimental hypertension in dogs

    • 1st to prove that renin system blockade would reduce hypertension

Basso, N. et al. Hypertension2001,38, 1246-1249.


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RENIN - HISTORY

  • 1970- Tadashi Inigami

    • Isolated pure renin from hog kidney

    • This was followed by isolation from rat and human kidney.

  • Currently working Vanderbilt University School of Medicine


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RENIN - STRUCTURE

  • Highly Species Specific

  • 340 amino acids

  • Two beta pleated sheets make two lobes

  • Active site between the two lobes

  • Aspartates for the active site provided by each lobe – i.e. Asp 32 and Asp. 215

ASP32

ASP215

Eder, J. et al. Current Pharmaceutical Design, 2007,13, 271-285.

PDB ID- 2v0z


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RENIN - FUNCTION

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu10--Val11-Ile-His-Asn---

Angiotensinogen (480 amino acid long)

Renin cleaves peptide bond

between Leu10-Val11

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu10 + Val11-Ile-His-Asn---

Angiotensin I


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RENIN - MECHANISM

ENZYME

ACTIVE SITE

Eder, J. et al. Current Pharmaceutical Design, 2007,13, 271-285.


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HOW DOES ONE MEASURE RENIN INHIBITION?

  • In Vitro

    • Human renin is incubated with inhibitor

    • Angiotensinogen is added.

    • Angiotensin I produced is measured by radioimmunoassay

  • In Vivo

    • Animal testing was done on sodium depleted marmosets

    • Now even transgenic rats are used

    • Changes in blood pressure and heart rate is measured telemetrically.

Image from - http://www.bukisa.com/articles/50597_marmoset-monkeys-and-their-habitats


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INHIBITORS OF RENIN


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INHIBITORS OF RENIN

  • Early Inhibitors of Renin

    • Antibodies

  • Transition State Analogs

    • Peptide Mimetic Inhibitors

    • Non-Peptide Inhibitors

      • Recently developed Inhibitors


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INHIBITORS OF RENIN

  • Early Inhibitors of Renin

    • Antibodies

  • Transition State Analogs

    • Peptide Mimetic Inhibitors

    • Non-Peptide Inhibitors

      • Recently developed Inhibitors


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EARLY INHIBITORS OF RENIN

  • Monoclonal Antibodies Against Renin

    • Excellent tools to study enzyme and its hypertensive effects

    • However –

      • parenteral administration

      • immunogenecitytherefore less application in medicine.

Galen, F. X. J. Clin. Invest. 1984,74, 723-735.


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INHIBITORS OF RENIN

  • Early Inhibitors of Renin

    • Antibodies

  • Transition State Analogs

    • Peptide Mimetic Inhibitors

    • Non-Peptide Inhibitors

      • Recently developed Inhibitors


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SCHECHTER AND BERGER NOMENCLATURE FOR PROTEASES

Mitti, P. R. Curr. Opin. Struct. Biol.2006, 16, 769-775.


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THEORY OF TRANSITION STATE ANALOGS

Transition

State

I

Enzyme Active Site

Inhibitor with

structure

similar to

transition state

will have high

affinity.

Energy

Product

Substrate

Reaction Co-ordinate

Schramm, V. L. Annu. Rev. Biochem. 1998,67, 693-720.


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PEPTIDE MIMETIC INHIBITORS

  • Modification of scissile bond with statine and its variants

    Normal Substrate: Angiotensinogen

    Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-]

    Statine Analog:

    Boc-Phe-His-Stat-Leu-Phe-NH2

Normal Peptide

IC50 – 190nM

Boger, J. et al. J. Med. Chem. 1985,28, 1779-1790.


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PEPTIDE MIMETIC INHIBITORS

Statine Analog:

Boc-Phe-His-Stat-Leu-Phe-NH2

ACHPA Analog:

Boc-Phe-His-ACHPA-Leu-Phe-NH2

IC50 – 49nM


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NON-PEPTIDE INHIBITORS OF RENIN

  • STORY OF ALISKIREN (DEVELOPED BY NOVARTIS)

  • DEVELOPMENT OF PIPERIDINE CLASS OF RENIN INHIBITORS (DEVELOPED BY HOFFMAN LA ROCHE AND OTHERS)


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NON-PEPTIDE INHIBITORS OF RENINSTORY OF ALISKIREN


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STORY OF ALISKIREN

Boc-Phe-His-ACHPA-Leu-Phe-NH2

CGP38560

IC50 = 1nM

  • The Renin-Angiotensin System; Robertson, J. I. S., Nicholls, M. G., Eds.; Mosby: London, 1993.


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STORY OF ALISKIREN

CGP38560

S1

S3

IC50 = 1nM

S3

S1

Goshke, R. et al. Bioorg. Med. Chem. Lett.1997, 7, 2735-2740.


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STORY OF ALISKIREN

Can be changed to methyl

-OCH2COOCH3 > -OCH2CONH2 > -OCH2COOH

-isopropyl was found optimum

Increase or decrease in substituent size caused decrease in activity

S1

S3

-phenyl substituent

equipotent to -t-butyl

R-epimer showed significant drop in activity


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STORY OF ALISKIREN

Most IC50 in μM range

IC50 = 20nM


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STORY OF ALISKIREN

To improve physicochemical properties


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STORY OF ALISKIREN

When R2 = -CH2CONH2

R3= -Me

R4= -n-butyl

Goshke, R. et al. J. Med. Chem. 2007, 50, 4818-4831.


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STORY OF ALISKIREN


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STORY OF ALISKIREN

Maibaum, J. et. al. J. Med. Chem. 2007,50, 4832-4844.


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STORY OF ALISKIREN


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STORY OF ALISKIREN

Aliskiren

Green= CGP38560

Purple= Aliskiren

Wood, J. M. et al. Biochem. Biophys. Res. Comm. 2003,308, 698-705.

PDB ID – 2v0z


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SUMMARY OF ALISKIREN

CGP38560

Aliskiren


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NON-PEPTIDE INHIBITORS OF RENIN-PIPERIDINE CLASS OF INHIBITORS


PIPERIDINE CLASS OF INHIBITORS

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Screening of the Roche Compound Library

IC50 = 50 μM

Highly selective for

renin.

Vieira, E. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1397-1402.


PIPERIDINE CLASS OF INHIBITORS

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  • X-Ray Structure Interpretation

Asp32-COOH

HOOC-Asp215

S4

S3

S1


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PIPERIDINE CLASS OF INHIBITORS

S4

S3

S1


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PIPERIDINE CLASS OF INHIBITORS

  • X-Ray Analysis

Asp32-COOH

HOOC-Asp215

Asp32-COOH

HOOC-Asp215

S3sp

S4

S1

S3

Lifts a whole flap region

fromThr72 to Ser81

S3

S1


PIPERIDINE CLASS OF INHIBITORS

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* Indicates point of attachment

to piperidine ring

S3sp

S3

S1

Guller, R. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1403-1408.


PIPERIDINE CLASS OF INHIBITORS

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S3sp

S1

S3

Story for these molecules in literature ends here

Marki, H. P. et al. Il Farmaco2001, 56, 21-27.


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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES

IC50 = 2nM

IC50 = 180nM

IC50 = 54nM

SAR studies

Holsworth, D. D. et al.Bioorg. Med. Chem.2005, 13, 2657-2664.


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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES

S3sp

S3

S1

Found to inhibit CYP3A4

* Indicates point of attachment to O.


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PIPERIDINE CLASS OF INHIBITORS-KETOPYRAZINES

S3sp

S3

S1

* Indicates point of attachment to N of tetrahydroquinoline

* Indicates point of attachment to N of tetrahydroquinoline

Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.


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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES

S3sp

S3

S1

* Indicates point of attachment to N of tetrahydroquinoline

* Indicates point of attachment to N of tetrahydroquinoline

Holsworth, D. D. et al.Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.


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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES

Tyr14

Tyr 14

H2O

Crystal Structure

Schematic View

Holsworth, D. D. et al. Bioorg. Med. Chem. Lett. 2006, 16, 2500-2504.

PDB ID – 2fs4


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PIPERIDINE CLASS OF INHIBITORS-KETOPIPERAZINES

S3sp

S3

S1

* Indicates point of attachment to C of Methyl


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SUMMARY OF PIPERIDINE CLASS


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RECENTLY DEVELOPED INHIBITORS OF RENIN

  • 3,9-diazobicyclo [3.3.1] nonene derivatives

Displaces H2O

from active site

aspartates

Bezencon, O. et al. J. Med. Chem. 2009, 52, 3689-3702.


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RECENTLY DEVELOPED INHIBITORS OF RENIN

  • 3,9-diazobicyclo [3.3.1] nonene derivatives

-H, -CH3, -cyclopropane

  • short linker preferred

  • ortho, meta substituents

  • improve

  • affinity.

  • ortho di-halo substituents preferred

  • 4-methyl group preferred

IC50 (nM) IC50 (nM)

Rec. Renin= 0.20 Plasma Renin= 19

Bezencon, O. et al. J. Med. Chem. 2009, 52, 3689-3702.


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RECENTLY DEVELOPED INHIBITORS OF RENIN

  • Alkyl amines

S3sp

HOOC-Asp32

HOOC-Asp215

S1

S3

Tice, C. M. et al. Bioorg. Med. Chem. Lett.2009, 19, 3541-3545.


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RECENTLY DEVELOPED INHIBITORS OF RENIN

  • Alkyl amines

3o alcohol would interact with Ser 219 γ Oxygen

-Me > -H

-Me> -Et

3-Cl > 3-F > 2-Cl > 2,3-diCl

Human Renin = 0.47 nM

Plasma Renin = 13 nM

Oral Bioavailability = 38%

(in dog)

Tice, C. M. et al. Bioorg. Med. Chem. Lett.2009, 19, 3541-3545.


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RECENTLY DEVELOPED INHIBITORS OF RENIN

  • Orally bioavailable alkyl amines- crystal structure

Tice, C. M. et al. Bioorg. Med. Chem. Lett.2009, 19, 3541-3545.

PDB ID = 3gw5


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FUTURE TARGET OF THE RENIN-ANGIOTENSIN SYSTEM


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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM

Involvement of Renin-Angiotensin System

  • Clearly not mediated

  • by Ang II.

  • Is there a

  • Renin Receptor?

Nguyen, G. et al. Curr. Opin. Nephrol. Hypertens. 2003, 12, 51-55.


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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM

Nguyen, G. et al. Journ. Clin. Invest. 2002, 109, 1417-1427

Image adapted from- http://tainano.com/Molecular%20Biology%20Glossary.files/image087.gif


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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM

  • Functionality of the receptor

    • Effect on Ang I generation in presence of renin

Membrane bound renin 1nM

Free renin 1nM

Membrane bound renin 0.5nM

Free renin 0.5nM

Agen = Angiotensinogen

Ang I = Angiotensin I


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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM

  • Functionality of the receptor

    • Effect on ERK1/ERK2 activation


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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM

  • Coronary

  • Artery

  • Immunofluorescence studies of receptors on cells of human:

    • Kidney

    • Placenta


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FUTURE TARGET OF RENIN ANGIOTENSIN SYSTEM

  • Characteristics of renin receptor:

    • 350 amino-acid protein with no homology

    • 45-kDa

    • Multidomain

      • Hydrophobic amino-terminal domainbinds renin and prorenin  activates it

      • Cytoplasmic tail= 20 amino acids  activates ERK1/ERK2 intracellularly

      • Single transmembrane domain

Campbell, D. J. Hypertension, 2008, 51, 1259-1264.


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CONCLUSION

Over 100 years since discovery of renin


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ACKNOWLEDGEMENTS

  • Dr. Umesh Desai

  • The Desai Group

  • Department of Medicinal Chemistry at VCU


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