Frontiers in Cardiovascular Drug Discovery: Volume 6

256 Pages·2022·27.703 MB·English

by  M. Iqbal Choudhary

Frontiers in Cardiovascular
Drug Discovery
(Volume 6)
Edited by
M. Iqbal Choudhary
H.E.J. Research Institute of Chemistry
International Center for Chemical and Biological Sciences
University of Karachi, Karachi
Pakistan
Frontiers in Cardiovascular Drug Discovery
Volume # 6
Editor: M. Iqbal Choudhary
ISSN (Online): 1879-6648
ISSN (Print): 2452-3267
ISBN (Online): 978-981-5036-90-9
ISBN (Print): 978-981-5036-91-6
ISBN (Paperback): 978-981-5036-92-3
©2022, Bentham Books imprint.
Published by Bentham Science Publishers Pte. Ltd. Singapore. All Rights Reserved.
First published in 2022.
BSP-EB-PRO-9789815036909-TP-243-TC-05-PD-20221110
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CONTENTS
PREFACE ................................................................................................................................................ i
LIST OF CONTRIBUTORS .................................................................................................................. iii
CHAPTER 1 CARDIOVASCULAR EFFECTS OF RANOLAZINE AND THE SCOPE FOR
TRANSLATIONAL RESEARCH: A CURRENT REVIEW OF LITERATURE ........................... 1
Rebecca Pratiti, Parul Sud, Mohammad Yousef and Ankush Moza
RANOLAZINE ............................................................................................................................... 2
MECHANISM OF ACTION ......................................................................................................... 3
Effects on Late Sodium Current ............................................................................................. 3
Effect on Metabolism .............................................................................................................. 3
Dosage Formulations, Pharmacodynamics and Pharmacokinetics ......................................... 5
Side Effects ............................................................................................................................. 6
General Side Effects ...................................................................................................... 6
Tolerability of Ranolazine ............................................................................................. 6
Drug-drug Interaction ................................................................................................... 7
QT-prolonging Effects ............................................................................................................ 8
Animal Studies ........................................................................................................................ 8
CHRONIC STABLE ANGINA (CSA) ......................................................................................... 13
ACUTE CORONARY SYNDROME (ACS) ................................................................................ 21
ATRIAL FIBRILLATION ............................................................................................................ 22
Rhythm Control for Atrial Fibrillation in the Presence and Absence of other Medications 24
Post-operative Atrial Fibrillation (POAF) in Patients Undergoing Cardiac Surgery ............. 25
CARDIOMYOPATHY .................................................................................................................. 25
Chemotherapy-induced Cardiomyopathy ............................................................................... 25
Hypertrophic Cardiomyopathy ............................................................................................... 26
ARRHYTHMIAS .......................................................................................................................... 26
LONG QT SYNDROMES (LQTS 3) ............................................................................................ 27
Pathophysiology ...................................................................................................................... 28
Efficacy ................................................................................................................................... 28
HEART FAILURE (HF) ................................................................................................................ 28
Pathophysiology ...................................................................................................................... 29
Heart Failure with Preserved Ejection Fraction (Diastolic) .................................................... 29
Heart Failure With Reduced Ejection Fraction (Systolic) ...................................................... 29
GLYCEMIC EFFECTS ................................................................................................................. 30
Mechanism of Action .............................................................................................................. 30
Effect on Glycated Hemoglobin A1c (HbA1c) ...................................................................... 31
Modifier effect of Metformin .................................................................................................. 31
OTHER ADDITIONAL EFFECTS OF RANOLAZINE ........................................................... 32
FUTURE IMPLICATIONS ........................................................................................................... 32
Gaps in Translational Research .............................................................................................. 35
Possible Causes of Inefficacy in Studies ................................................................................ 38
CONCLUSION AND SUMMARY ............................................................................................... 39
LIST OF ABBREVIATIONS ........................................................................................................ 39
CONSENT FOR PUBLICATION ................................................................................................ 42
CONFLICT OF INTEREST ......................................................................................................... 42
ACKNOWLEDGEMENTS ........................................................................................................... 42
REFERENCES ............................................................................................................................... 42
CHAPTER 2 RHO/RHO KINASE SIGNALING PATHWAY AND DISEASE: FROM BED TO
BENCH ..................................................................................................................................................... 54
Yiming Wang, Yuqing Zhang and Dingguo Zhang
INTRODUCTION .......................................................................................................................... 55
BIOLOGICAL EFFECTS OF RHO PROTEIN ......................................................................... 55
Rho Protein Classification ...................................................................................................... 55
Rho Protein Structure and Activity Regulation ...................................................................... 56
Downstream Effector Molecules of Rho ................................................................................ 56
RHO KINASE ................................................................................................................................. 57
Structure and Classification of Rho Kinases .......................................................................... 57
Regulation Mechanism of Rho Kinase Activity ..................................................................... 59
Rho Kinase Inhibitor ............................................................................................................... 59
RHO/RHO KINASE AND CARDIOVASCULAR DISEASE ................................................... 60
Rho/Rho Kinase and Hypertension ......................................................................................... 60
Rho/Rho Kinase and Pulmonary Hypertension ...................................................................... 61
Rho/Rho Kinase and Atherosclerosis ..................................................................................... 62
Rho/Rho Kinase and Myocardial Ischemia Reperfusion Injury ............................................. 63
Rho/Rho Kinase and Adriamycin-induced Heart Injury ........................................................ 64
Outlook ................................................................................................................................... 65
RHO KINASE AND ISCHEMIC CEREBROVASCULAR DISEASE .................................... 65
The Mechanism of Rho Kinase in Cerebral Ischemia ............................................................ 66
Rho Kinase Mediates Oxidative Stress ......................................................................... 66
Rho Kinase Mediated Cytoskeleton Changes ............................................................... 67
Rho Kinase Mediates Inflammatory Response .............................................................. 67
Rho Kinase Regulates Phosphatidylinositol Metabolism ............................................. 68
Rho Kinase Regulates the Expression of eNOS ............................................................ 68
Rho Kinase Regulates the Expression of Matrix Metalloproteinase-9 ......................... 69
Neuroprotective Effect of Rho Kinase Inhibitor ..................................................................... 69
Outlook ................................................................................................................................... 70
RHO KINASE AND RESPIRATORY DISEASES ..................................................................... 70
Rho Kinase and COPD ........................................................................................................... 70
Rho Kinase and Asthma .......................................................................................................... 71
Rho Kinase and IPF ................................................................................................................ 72
Rho Kinase and Lung Cancer ................................................................................................. 72
Conclusion and Prospect ......................................................................................................... 73
RHO KINASES IN IMMUNE CELLS AND AUTOIMMUNE DISEASES ............................ 73
Rho/ROCK Signaling Pathway in Systemic Lupus Erythematosus ....................................... 75
Rho/ROCK Signaling Pathway in Rheumatoid Arthritis ....................................................... 76
Rho/ROCK Signaling Pathway in Systemic Sclerosis ........................................................... 77
CONCLUSION ............................................................................................................................... 77
RHO AND CHRONIC KIDNEY DISEASE ................................................................................ 77
Rho/ROCK in 5/6 Nephrectomy and Unilateral Ureteral Ligation Model ............................. 78
Rho/ROCK in Hypertensive Nephropathy Animal Model ..................................................... 79
Rho/ROCK in Diabetic Animal Model ................................................................................... 79
Rho/ROCK in Contrast Medium Induced Kidney Injury Model ............................................ 80
RHO AND PORTAL HYPERTENSION ..................................................................................... 80
OUTLOOK ...................................................................................................................................... 83
CONCLUSION ............................................................................................................................... 83
ABBREVIATIONS ......................................................................................................................... 84
CONSENT FOR PUBLICATION ................................................................................................ 85
CONFLICT OF INTEREST ......................................................................................................... 85
ACKNOWLEDGEMENTS ........................................................................................................... 85
REFERENCES ............................................................................................................................... 85
CHAPTER 3 HIBERNATION OR TRANSFORMATION? CHALLENGES IN
CARDIOVASCULAR DRUG DEVELOPMENT ................................................................................ 102
G. Mercanoglu and F. Mercanoglu
INTRODUCTION .......................................................................................................................... 102
DEVELOPING NEW DRUGS IN THE 21 st CENTURY ........................................................ 104
CHALLENGES IN DRUG DEVELOPMENT AND THEIR REFLECTIONS ON THE
CARDIOVASCULAR FIELD ....................................................................................................... 105
DISCOVERY AND DEVELOPMENT ................................................................................. 105
Challenges in Strategic Decision Making ..................................................................... 107
Challenges in Preclinical Trials ................................................................................... 108
CLINICAL DEVELOPMENT ............................................................................................... 112
Challenges in Clinical Trials ........................................................................................ 113
REGULATORY APPROVAL ............................................................................................... 122
Regulatory Uncertainty ................................................................................................. 123
Health-related Economic Challenges ........................................................................... 125
FINANCIAL CHALLENGES ................................................................................................ 126
Return Potential of Investment ...................................................................................... 126
Patent Cliff .................................................................................................................... 126
Insufficient Incentives (Funding) .................................................................................. 128
Insufficient Investment .................................................................................................. 129
Late-stage Failures ....................................................................................................... 131
CONCLUSION AND FUTURE PERSPECTIVE ....................................................................... 132
CONSENT FOR PUBLICATION ................................................................................................ 133
CONFLICT OF INTEREST ......................................................................................................... 133
ACKNOWLEDGMENTS .............................................................................................................. 133
REFERENCES ............................................................................................................................... 133
CHAPTER 4 NEW APPROACHES IN P2Y1 2 R ECEPTOR BLOCKER DRUGS USE . ............. 141
Dolunay Merve Fakioğlu and Sevgi Akaydin
PRIMARY AND SECONDARY HEMOSTASIS ........................................................................ 141
P2Y1 AND P2Y12 (ADP RECEPTORS) ...................................................................................... 144
P2Y12 RECEPTOR INHIBITORS AND POTENTIAL CLINICAL USE ............................... 145
Stable Ischemic Heart Disease ................................................................................................ 147
Acute Coronary Syndromes .................................................................................................... 149
Secondary Prevention of Ischemic Stroke .............................................................................. 150
Prosthetic Heart Valves Triple Treatment .............................................................................. 152
PRECISION MEDICINE IN DUAL ANTIPLATELET REGIMES STRATEGIES (DE-
ESCALATION, ESCALATION, CHANGE STRATEGIES FOR DUAL ANTIPLATELET
THERAPY) ..................................................................................................................................... 152
De-Escalation via a Duration of Dual Antiplatelet Treatment ................................................ 152
De-Escalation with Switching Between P2y12 Inhibitors Drugs ........................................... 156
De-escalation with Dose Reduction ........................................................................................ 167
Escalation ................................................................................................................................ 167
Change Between Prasugrel and Ticagrelor ............................................................................. 168
Triple Antithrombotic Therapy ............................................................................................... 169
PRECISION MEDICINE ON P2Y12 INHIBITORS WITH GENE TESTING APPROACH
AND CLOPIDOGREL RESISTANCE ........................................................................................ 172
P2Y12 Receptor Gene Polymorphisms .................................................................................. 175
CONCLUSION ............................................................................................................................... 176
CONSENT FOR PUBLICATION ................................................................................................ 177
CONFLICT OF INTEREST ......................................................................................................... 177
ACKNOWLEDGEMENTS ........................................................................................................... 177
REFERENCES ............................................................................................................................... 177
CHAPTER 5 PATHOPHYSIOLOGICAL LINKS BETWEEN DIABETES AND
CARDIOVASCULAR DISEASES: AT THE BIOCHEMICAL AND MOLECULAR LEVELS 191
M.M. Towhidul Islam and Yearul Kabir
INTRODUCTION .......................................................................................................................... 191
EPIDEMIOLOGICAL STUDIES ................................................................................................. 192
STRUCTURAL AND FUNCTIONAL CHANGES OF CARDIAC TISSUE DURING
DIABETES ...................................................................................................................................... 193
Role of Obesity in Diabetes and CVD .................................................................................... 196
Role of Glycemic Control in Diabetes and CVD .................................................................... 197
Role of Dyslipidemia in Diabetes and CVD ........................................................................... 197
Role of Hypertension in Diabetes and CVD ........................................................................... 198
BIOCHEMICAL ASPECTS BETWEEN DIABETES AND CVDS .......................................... 199
MOLECULAR ASPECTS BETWEEN DIABETES AND CVDS ............................................. 200
Genetic Loci Linked with T2DM and CVD ........................................................................... 202
DNA or Histone Modifications in T2DM and CVDs ............................................................. 203
Association of HMGA1 with T2DM and CVD Risk .............................................................. 204
Association of MicroRNAs (miRNA) with T2DM and CVD Risk ........................................ 204
Association of Long Non-Coding RNA (lncRNAs) with T2DM and CVD Risk .................. 207
PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE IN DIABETES
MELLITUS ..................................................................................................................................... 208
LESSONS LEARNED AND FUTURE DIRECTIONS .............................................................. 213
CONCLUSION ............................................................................................................................... 213
CONSENT FOR PUBLICATION ................................................................................................ 213
CONFLICT OF INTEREST ......................................................................................................... 214
ACKNOWLEDGEMENTS ........................................................................................................... 214
REFERENCES ............................................................................................................................... 214
SUBJECT INDEX .................................................................................................................................... 2(cid:22)(cid:19)
i
PREFACE
Despite major developments in the early diagnosis and understanding of underlying molecular
mechanisms, cardiovascular diseases (CVDs) remain the leading cause of death (31% death
globally), followed by cancers. The risk of developing CVDs is highest among all non-
communicable diseases. It has increased multi-fold with the increase in prevalence of
metabolic disorders, including obesity. CVDs affect people of all regions and all ages, and
there are many socio-demographic risk factors. Despite major basic research in this area,
translating laboratory discoveries into therapeutic interventions remains a major challenge,
and only a handful of drugs have reached to clinical application. Thus drug development
against cardiovascular diseases has many unique challenges which large pharmaceutical
companies are often not willing to address. The 6th volume of the book series entitled,
“Frontiers in Cardiovascular Drug Discovery” is a compilation of five reviews on diverse
topics, including translational research towards improved drugs, various molecular pathways
and biomarkers to be targeted for the drug discovery as well as challenges in cardiovascular
drug development.
The review by Pratiti et al is focused on the piperazine-based drug ranolazine for the
treatment of various cardiovascular diseases. Ranolazine was initially developed as an oral
antianginal medicine, and later identified as a versatile cardiovascular drug against various
indications. The authors have provided a detailed account of translational research work
carried out on ranolazine for a whole range of other CVDs. In the second chapter Zhang et al
have emphasized the importance of Rho/Rho kinase (ROCK) as an important drug target.
Rho/Rho kinase is related to cardiovascular conditions such as coronary atherosclerosis,
hypertension, and heart failure. Selective inhibitors of ROCK can treat many CVDs. This
article presents the relationship between various CVDs and Rho/Rho kinase, and thus
validates this as a legitimate drug target. Numerous examples of ROCK inhibitors with
potential as drugs are also presented.
The review article of G. Mercanoglu and F. Mecanoglu provides a comprehensive account of
major challenges and bottlenecks in CVD drug development, that have resulted in a huge
vacuum in this drug pipeline. The authors have commented on reasons of a gradual shift of
CVD drug development from large pharmaceutical companies to medium pharma industries,
small biotech firms and research and development institutions. A field which was historically
considered as a “profitable” area of therapeutic research and development now needs support
from World Health Organizations and other NGOs. With this background, the authors have
provided some logical solutions to overcome the existing problems. Platelet P2Y12 receptor
(P2Y12R) for adenosine 5'diphosphate (ADP) plays a central role in platelet function,
hemostasis, and thrombosis. Akaydin et al have discussed various approaches to inhibit
P2Y12 receptors for the prevention of platelet aggregation and thrombosis. These inhibitors
can also prevent and treat ischemic complications in patients with unstable angina,
myocardial infarction and coronary intervention. Various classes of P2Y12 inhibiting drugs
and their clinical outcomes are discussed. Kabir et al have contributed a comprehensive
review on the nexus of diabetes and cardiovascular diseases such as atherosclerosis,
hypertension and myocardial infarction. CVD is the most prevalent cause of mortality in the
diabetic population. The authors have also provided a detailed account of the mechanisms of
the onset of these diseases. Studies of the molecular mechanisms involved in the progression
of CVDs in diabetes as well as biomarker identification can not only contribute to the early
diagnosis and prevention of the disease, but it can also help in the novel target identification
for anti-diabetic and anti-CVD drug development.