The document presents information on the development of rho kinase inhibitors for cardiovascular disorders, highlighting the role of rho kinase (ROCK) in signal transduction and smooth muscle contraction. It discusses the activation of ROCK, its regulatory mechanisms, and the implications of ROCK inhibitors in treating cardiovascular issues and glaucoma. Additionally, it references various studies supporting the therapeutic potential of rho kinase inhibition.

1. DEVELOPMENT OF Rho KINASE
INHIBITORS FOR CVS DISORDERS
Presented by:
Biswajit Panda
PC/2017-X/178
Pharmacology & Toxicology
Niper Guwahati

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CONTENTS

3. What is Rho ?
Concept of Rho kinase .
How Rho kinase is activated ?
What are Functions of Rho kinase ?
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4. What is Rho ?
Rho stands for
Ras homolog
gene family.
It is a family
of small
signalling G-
proteins
It is
subfamily of
Ras super
family.
Signalling
pathway
for varios agonists
like
AT-ll,5-HT, ET-1,
Histamine,TXA2.
FUNCTIONS
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5. Rho
Rho
Rho GDP
GDP
Rho GDP
Prenyl
transferase
GDP
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GDI
GDI
GDI
Rho GTP
GAPGEF

6. Concept of Rho kinase
• Rho kinase (ROCK) are the serine/threonine kinases.
• Belonging to AGC family of protein kinase.
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About Structure…
a) N-Terminal kinase/catalytic domain
b) A central Coiled coil domain
containing RBD
c) C-Terminal pleckstrin homology
domain interrupted by a cys – rich
region

7. • In the inactive form the PH and
RBD domain (C –terminal ) bind to
the amino terminus of the enzyme,
forming an autoinhibitory loop
hence it is called negative
regulatory region of Rho-kinase.
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8. How Rho kinase is activated ?
•After the translocation of Rho to membrane GDP converts to GTP and binf
to the Rho binding domain of ROCK .
•Arachidonic acid and caspase/granzyme activating Rho.
Rho kinase
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Rho-GTP

9. Regulation of ROCK –
• Small GTPase RhoE binds to the N-terminal part of ROCK I and
interferes with binding of Rho.
•Small G-proteins, Gem and Rad, have also been shown to bind to and
thereby inhibit ROCKs.
•PDK1 directly binds to ROCK1 in competition with RhoE, leading to the
release of ROCK1 from RhoE and activation of ROCK.
ROCK
RhoE
GEM
RAD
PDK1
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10. What are Functions of Rho kinase ?
Rho GTP ROCK MLC MLC P
Adducin
ERM LMK
MLCP
Contraction of
actin fibres
Actin
depolymerisation
Cofilin Cofilin
Filament
stabilization
P
G12/13 Gq
PKC
MLCK
CAM
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11. Smooth muscle contraction by ROCK
MBS MBS
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12. ROCK
MLCph
PAI1
PI3K
Contractile tone
Hypertension
Coronary vasospasm
Cerebral vasospasm
Atherogenesis
eNOS
NO
Endothelial
Dysfunction
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13. • Fasudil
• Ripasudil
• RKI1447
• Y27632
• Statins
• PPIs
Rho kinase
Inhibitors
Fasudil
Statins
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14. Uses of ROCK inhibitors
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15. • Wirth A. Rho kinase and hypertension. Biochimica et Biophysica Acta (BBA)-
Molecular Basis of Disease. 2010 Dec 31;1802(12):1276-84.
• Surma M, Wei L, Shi J. Rho kinase as a therapeutic target in cardiovascular
disease. Future cardiology. 2011 Sep;7(5):657-71.
• Amano M, Nakayama M, Kaibuchi K. Rho kinase/ROCK: a key regulator of‐
the cytoskeleton and cell polarity. Cytoskeleton. 2010 Sep 1;67(9):545-54.
• Shimokawa H, Rashid M. Development of Rho-kinase inhibitors for
cardiovascular medicine. Trends in pharmacological sciences. 2007 Jun
30;28(6):296-302.
• Challa P, Arnold JJ. Rho-kinase inhibitors offer a new approach in the
treatment of glaucoma. Expert opinion on investigational drugs. 2014 Jan
1;23(1):81-95.
• Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase
inhibitors. Clinical Ophthalmology (Auckland, NZ). 2014;8:883.
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KEEP A HEALTHY
HEART