The Editors
Prof. Dr. János Fischer
Richter Plc
Gyömröi ut 30
1103 Budapest
Hungary
Prof. Dr. C. Robin Ganellin
University College London
Department of Chemistry
20 Gordon Street
London WC1H OAJ
United Kingdom
Supported by
The International Union of Pure and Applied
Chemistry (IUPAC)
Chemistry and Human Health Devision
PO Box 13757
Research Triangle Park, NC 27709-3757
USA
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ISBN: 978-3-527-32549-8
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Contents
Cover
Title Page
Copyright
Related Titles
Preface
Introduction
Abbreviations
Part I - General Aspects
1 - Optimizing Drug Therapy by Analogues
1.1 - Introduction
1.2 - Pharmacodynamic Characteristics
1.3 - Pharmacokinetic Characteristics
1.4 - Drug Interactions
1.5 - Summary
Acknowledgments
References
2 - Standalone Drugs
2.1 - Acetaminophen (Paracetamol)
2.2 - Acetylsalicylic Acid (Aspirin)
2.3 - Aripiprazole
2.4 - Bupropion
2.5 - Ezetimibe
2.6 - Lamotrigine
2.7 - Metformin
2.8 - Topiramate
2.9 - Valproate
2.10 - Summary
Acknowledgment
References
3 - Application of Molecular Modeling in Analogue-Based Drug Discovery
3.1 - Introduction
3.2 - Cilazapril: An ACE Inhibitor
3.3 - Atorvastatin: A HMG-CoA Reductase Inhibitor
3.4 - PDE4 Inhibitors
3.5 - GPIIb/IIIa Antagonists
3.6 - HIV Protease Inhibitors
3.7 - Epilogue
References
4 - Issues for the Patenting of Analogues
4.1 - Introduction
4.2 - Patents: Some Fundamentals
4.3 - Patentability
4.4 - Important Elements of the International Patent System
4.5 - Priority
4.6 - Novelty
4.7 - Inventive Step: Nonobviousness
4.8 - Utility: Industrial Application
4.9 - Selection Inventions
4.10 - Enantiomers
4.11 - Prodrugs and Active Metabolites
4.12 - The Patenting Process from the Inventor.s Standpoint
4.13 - Pitfalls for the Unwary: Granted Versus Published Patents, Scientific Publications
Appendix 4.A - Some Patent Jargon Terms
Appendix 4.B - A Typical Broad Chemical Claim
Appendix 4.C - Further Reading
References
Part II - Analogue Classes
5 - Dipeptidyl Peptidase IV Inhibitors for the Treatment of Type 2 Diabetes
5.1 - Introduction
5.2 - In Vitro Assays and Animal Models for the Assessment of DPP-IV Inhibitors
5.3 - Substrate-Based DPP-IV Inhibitors
5.4 - Sitagliptin and Analogues
5.5 - Xanthines and Analogues
5.6 - Pharmacological Comparison of DPP-IV Inhibitors
5.7 - Concluding Remarks
References
6 - Phosphodiesterase 5 Inhibitors to Treat Erectile Dysfunction
6.1 - Introduction
6.2 - Pharmacology of Phosphodiesterases
6.3 - Pyrimidinone PDE5 Inhibitors
6.4 - Nonpyrimidone PDE5 Inhibitors
6.5 - Conclusions
References
7 - Rifamycins, Antibacterial Antibiotics and Their New Applications
7.1 - Discovery of the Pioneer Drug
7.2 - Clinically Used Rifamycins
7.3 - Mode of Action of Rifamycins and Structural Requirements for Activity
7.4 - Modulation of Chemotherapeutic Properties
7.5 - Profiles of Rifamycins Targeted at Tuberculosis Treatment
7.6 - Rifampicin (INN), Rifampin (USAN)
7.7 - Rifapentine
7.8 - Rifabutin
7.9 - Rifamycins Beyond Tuberculosis
7.10 - Rifamycin SV and Rifamide
7.11 - Rifaximin
7.12 - Trials for Other Therapeutic Indications
7.13 - Summary
References
8 - Monoterpenoid Indole Alkaloids, CNS and Anticancer Drugs
8.1 - Introduction
8.2 - Vincamine and Derivatives: Cerebrovascular and Neuroprotective Agents
8.3 - Antitumor Dimeric Vinca Alkaloids
8.4 - Antitumor Camptothecin Derivatives
8.5 - Summary and Conclusions
References
9 - Anthracyclines, Optimizing Anticancer Analogues
9.1 - Introduction: Biosynthetic Antitumor Anthracyclines
9.2 - Analogues with Modification of the Aminosugar Moiety
9.3 - Analogues with Modifications in the Anthraquinone Moiety
9.4 - Analogues Modified on Ring A of the Aglycone
9.5 - Disaccharide Analogues
9.6 - Other Compounds
9.7 - Summary and Final Remarks
References
10 - Paclitaxel and Epothilone Analogues, Anticancer Drugs
10.1 - Introduction
10.2 - Discovery and Development of Paclitaxel
10.3 - Clinical Success and Shortcomings of Paclitaxel
10.4 - ABDD Leading to Docetaxel
10.5 - Additional Structural Analogues
10.6 - The Pursuit of Microtubule-Stabilizing Pharmacological Analogues
10.7 - The Epothilones
10.8 - ABDD and Development Leading to Ixabepilone
10.9 - Conclusions
Acknowledgments
References
11 - Selective Serotonin Reuptake Inhibitors for the Treatment of Depression
11.1 - Introduction
11.2 - Neurochemistry and Mechanism of Action
11.3 - Preclinical Pharmacology
11.4 - Medicinal Chemistry
11.5 - Comparison of SSRIs and Other Uses
11.6 - Summary
References
12 - Muscarinic Receptor Antagonists in the Treatment of COPD
12.1 - Introduction
12.2 - Muscarinic Receptor Subtypes
12.3 - Structures of Muscarinic Agonists and Antagonists
12.4 - Preclinical Pharmacology: Comparison of Ipratropium and Tiotropium
12.5 - Clinical Pharmacology
12.6 - Antimuscarinics in Clinical Development for the Treatment of COPD
12.7 - Summary
Acknowledgment
References
13 - b-Adrenoceptor Agonists and Asthma
13.1 - Introduction
13.2 - First-Generation b2-Agonists: The Short-Acting Bronchodilators
13.3 - Second-Generation b2-Agonists: Further Derivatives of Salbutamol
13.4 - Third-Generation b2-Agonists: The Long-Acting Bronchodilators
13.5 - Combination Therapy with LABA and Corticosteroids
13.6 - Future Directions: Once-a-Day Therapy and Bifunctional Muscarinic Antagonist–b2-Agonist (MABA)
Acknowledgments
References
Part III - Case Histories
14 - Liraglutide, a GLP-1 Analogue to Treat Diabetes
14.1 - Introduction
14.2 - Discussion
14.3 - Summary
References
15 - Eplerenone: Selective Aldosterone Antagonist
15.1 - Introduction
15.2 - Development of a Specific and Selective Aldosterone Antagonist
15.3 - Eplerenone: Selectivity and Specificity
15.4 - Preclinical Development of Eplerenone: From Animal to Man
15.5 - Further Development of Eplerenone
15.6 - Conclusions
15.7 - Epilogue
References
16 - Clevudine, to Treat Hepatitis B Viral Infection
16.1 - Current Status of Anti-HBV Agents
16.2 - Chemical Evolution of Clevudine
16.3 - Metabolism and Mechanism of Action
16.4 - Pharmacokinetics
16.5 - Clinical Studies
16.6 - Drug Resistance
16.7 - Toxicity and Tolerability
16.8 - Dosage and Administration
16.9 - Combination Therapy
16.10 - Summary
Acknowledgments
References
17 - Rilpivirine, a Non-nucleoside Reverse Transcriptase Inhibitor to Treat HIV-1
17.1 - Introduction
17.2 - Chemistry
17.3 - Structure–Activity Relationships
17.4 - TMC278: Physicochemical Properties
17.5 - Modeling of TMC278 and Crystal Structure
17.6 - Pharmacokinetic and Phase II Studies of TMC278
17.7 - Conclusions
Acknowledgments
References
18 - Tipranavir, a Non-Peptidic Protease Inhibitor for Multi-drug Resistant HIV
18.1 - Human Immunodeficiency Virus
18.2 - HIV Protease
18.3 - Approaches to Identifying and Developing PI Leads
18.4 - Characteristics of Tipranavir
18.5 - Fragment-Based Lead Development?
18.6 - Summary
References
19 - Lapatinib, an Anticancer Kinase Inhibitor
19.1 - Introduction
19.2 - Aims
19.3 - Chemical Evolution and Proof-of-Mechanistic Approach Using Small Molecules
19.4 - Final Set of Analogues that Led to the Discovery of Lapatinib
19.5 - Final Selection Criteria and Data
19.6 - Early Clinical Results
19.7 - Prospects for Kinase Inhibitors
Acknowledgments
References
20 - Dasatinib, a Kinase Inhibitor to Treat Chronic Myelogenous Leukemia
20.1 - Introduction
20.2 - Discussion
20.3 - Clinical Findings and Summary
References
21 - Venlafaxine and Desvenlafaxine, Selective Norepinephrine and Serotonin Reuptake Inhibitors to Treat Major Depressive Disorder
21.1 - Introduction
21.2 - Major Depressive Disorder
21.3 - MDD Pharmacotherapy
21.4 - The Discovery of Venlafaxine
21.5 - Clinical Efficacy of Effexor®
21.6 - An Extended Release Formulation – Effexor XR1
21.7 - Discovery of a Second-Generation SNRI – O-Desmethylvanlafaxine
21.8 - Effexor and Pristiq – Additional Considerations
21.9 - Conclusions
References
Index
Preface
The positive response to the first volume stimulated the editors to continue beyond the well-received book.
Three very important facts supported this feeling.
1) All copies of the book “Analogue-Based Drug Discovery” were sold within 18 months after its publication in February 2006.
2) The Journal of Medicinal Chemistry in its very positive review recommended the book for teaching of medicinal chemistry.
3) Last, but not the least Wiley-VCH, and, personally, Dr. Frank O. Weinreich welcomed the idea of the continuation.
We started to collect new topics at the beginning of 2008. We have continued to study the general aspects of “Analogue-Based Drug Discovery” with the help of the chapters that describe how analogues optimize drug therapy. In a separate chapter on standalone drugs, we demonstrate that in the case of a minor number of drugs, the pioneer drug could not (or not yet) be optimized. These standalone drugs can always challenge the medicinal chemistry researchers because, as existing drugs, they can serve as starting points for researchers.
We are grateful again to the IUPAC (International Union of Pure and Applied Chemistry), which supported this activity in projects. The Subcommittee for Medicinal Chemistry and Drug Development and the Division of Chemistry and Human Health provided the opportunity to the editors to discuss this work with other experts of medicinal chemistry.
We are grateful for the participation of all the contributors. Many authors of the book played an important role as inventors who discovered valuable drugs, and their chapters carry a high credibility either as an analogue class study or as a case history of a drug.
We are very much obliged to the helpful reviewing work done by many colleagues, whose names are as follows: Karl-H. Baringhaus, Jozsef Bódi, Derek Buckle, Mark Bunnage, Duane Burnett, Neal Castagnoli, Jonathan B. Chaires, Mukund Chorghade, Erik De Clercq, Duncan Curley, György Domány, Joelle Dubois, Andrew Fensome, Tom Heightman, Bastian Hengerer, Duy H. Hua, Robert Jones, Dale Kempf, Karsten Krohn, K.H. Lee, John Lowe III, Frank C. Odds, Eckhard Ottow, Tom Perun, István Polgár, Dominick Quagliato, Waldemar Priebe, Graham Robertson, Romano Silvestri, László Szabó, Károly Tihanyi, Edwin B. Villhauer, Niels Vrang, Richard White, Michael Williams, and Puwen Zhang. All these colleagues contributed to the quality of this second volume.
We express special thanks to reviewers Derek Buckle, John Lowe III, Bruce E. Maryanoff, Lester A. Mitscher, and Dominick Quagliato, who each corrected the language, and Eckhard Ottow, who corrected the structures, of a whole chapter.
Some authors, besides the editors, also served as reviewers. Our thanks are due to these authors and reviewers as follows: Giovanni Gaviraghi, John Proudfoot, and David Rotella.
J.F. thanks the Alexander von Humboldt Foundation (Bonn) for a fellowship in 2008 and 2009.
We hope that the second volume will also be well received and that it will contribute in some way to help the experts in drug discovery and students of medicinal chemistry.
János Fischer and C. Robin Ganellin
October 2009
Budapest and London
Introduction
János Fischer and C. Robin Ganellin
Analogy plays a very important role in scientific research and especially in applied research. This is certainly true for the medicinal chemist searching for new drugs to treat diseases. The chemical structure and the similarities and differences in chemical and biological properties between compounds help guide the researcher in deciding where to position a new molecule in comparison to what is already known about other compounds.
Medicinal chemistry is a relatively “young” science that spanned the whole of the twentieth century. In the first half of the century, new drug research was dominated by organic chemistry, and researchers sought improved drugs among structurally similar compounds. Full analogues (see below) dominated this kind of research. The latter half of the century saw a much greater contribution from biochemistry and pharmacology, and many pioneer drugs were discovered. This opened the way for researchers to seek to improve upon these drugs by investigating analogues.
The first volume of Analogue-Based Drug Discovery focused on an important segment of medicinal chemistry, where an existing drug was selected as a lead compound and the research had, as a goal, to improve upon the lead by synthesizing and testing analogues. The chemical structure and main biological activity of such an analogue were often similar to the lead drug. Thus, the researchers generally sought a structural and pharmacological analogue (more simply called a full analogue) or if the pharmacophores were the same, a direct analogue. Usually, the aim was to achieve an improved biological activity profile, with a greater potency.
The first volume included a description of many well-established analogue classes of drug that are indispensable nowadays for the treatment of peptic ulcer disease, gastroesophageal reflux disease, prevention of cardiovascular diseases (e.g., antihypertensives, cholesterol-lowering agents, calcium antagonists, and beta-adrenergic receptor blocking agents), pain (e.g., opioid analgesics), and many other diseases.
The last two decades, however, have witnessed great changes in the chemical and biological methods for generating a lead compound. Combinatorial chemistry affords many more compounds than traditional synthetic methods and these are tested very rapidly by high-throughput screening (HTS) to deliver new hit and lead molecules. This procedure often paves the way for new types of structures for drug research thereby decreasing the importance of having chemical similarity. At the same time, this provides a better opportunity for novelty and therefore for patenting. This also gives rise to a greater need to compare the biological properties of these new lead compounds in order to arrive at the best pharmacological analogue.
Analogue-based drug discovery (ABDD) is not a simple research method, but it is a way of thinking that, in addition to organic synthesis, uses most of the procedures that are now available to medicinal chemists, such as
i. investigation of structure–activity relationships,
ii. molecular modeling,
iii. structure-based drug discovery,
iv. fragment-based drug discovery,
v. early recognition of drug distribution properties and avoidance of potential toxicities.
Analogue-based drug discovery has the merit that the therapeutic target is already validated, but it carries the hazard of potentially losing out to competitors who may start from the same approach at about the same time.
This second volume of Analogue-Based Drug Discovery has a broader scope than the first volume. The book not only contains descriptions of full analogues but also includes several pharmacological analogues. The book is divided into three parts:
1) General Aspects of Analogue-Based Drug Discovery
2) Analogue Classes
3) Case Histories
General Aspects
The opening chapter summarizes various possibilities exemplifying how the properties of a drug may be modified to give a new drug analogue that improves patient drug therapy. There are 12 principles exemplified and within some of these principles there are several methods; hence this chapter gives a broad overview.
A small number of the pioneer drugs remain without successful analogues; we describe these by the term standalone drugs. Among the most frequently used 100 drugs, 9 such standalone drugs can be identified. Their history and present situation may be used to initiate a new research activity to make their analogues.
In addition to the traditional structure–activity relationship (SAR) studies, molecular modeling is the most important method that can help the medicinal chemist to find a new drug analogue. The chapter discusses several useful examples of molecular modeling in analogue research.
Patenting activity is one of the basic tasks of drug research. Patents mostly concern a group of direct analogues; therefore, the first claim of a patent contains a general structure that describes this group of compounds. The chapter gives an overview of some of the issues that can affect the commercial protection of the discoveries made by medicinal chemists.
Analogue Classes
The discovery of dipeptidyl peptidase IV inhibitors has opened a promising chapter for the treatment of type 2 diabetes. The pioneer drug sitagliptin has been followed by several analogues in order to obtain more potent and longer acting derivatives.
Serendipitous clinical observation afforded the pioneer drug sildenafil. Several analogues have been found that have optimized its properties (e.g., selectivity, duration of action).
Rifamycins are antibacterial antibiotics derived from fermentation. Analogue-based drug research afforded more potent derivatives. One of the derivatives, the poorly absorbed rifaximin, has a promising application for the treatment of irritable bowel syndrome.
Three analogue classes of monoterpenoid indole alkaloids are discussed: (i) vincamine derivatives, (ii) dimeric vinca alkaloid analogues, and (iii) camptothecin analogues. The successful natural product direct analogues are applied for the treatment of cerebral insufficiencies and cancer.
The natural product doxorubicin is an anthracycline antibiotic used to treat a wide range of cancers, but it has a cardiotoxic adverse effect. The research into direct analogues had a goal to obtain drugs with a better therapeutic index.
Paclitaxel and epothilone analogues are also examples of how natural product drugs can be used to initiate analogue-based drug research to afford new drug analogues with better properties as anticancer agents.
The selective serotonin reuptake inhibitors (SSRIs) are pharmacological analogues that revolutionized antidepressant therapy. The structurally different SSRIs have different profiles for inhibiting uptake of the neurotransmitters: serotonin, dopamine, and norepinephrine.
The modification of naturally occurring tropane alkaloids afforded the quaternary ammonium salts ipratropium and tiotropium, which are important drugs used for treating chronic obstructive pulmonary disease. Tiotropium, as a result of analogue-based drug discovery, has a longer duration of action that enables a once-daily dosing.
The natural product adrenaline (epinephrine) was the starting point for drug research into β-adrenoreceptor agonists. From isoprenaline (isoproterenol) through the selectively acting salbutamol, and on to salmeterol, analogue research resulted in selective, more potent, and longer acting analogues with different PK profiles, which are important drugs in asthma therapy.
Case Histories
Eight case histories are described by their inventors.
Liraglutide is a new antidiabetic drug, an analogue of the natural product glucagon-like peptide 1. Among the acylated GLP-1 analogues liraglutide has been developed for a once-daily treatment.
Eplerenone is a spironolactone analogue for treating hypertension that has a greater selectivity for the mineralocorticoid receptor and reduced sexual side effects.
Clevudine is a new drug for the treatment of the chronic hepatitis B virus (HBV) infection, which belongs to the class of nucleoside reverse transcriptase inhibitors.
Tipranavir is a new anti-HIV agent that is a protease inhibitor. The discovery of tipranavir used structure-based and fragment-based drug design and its long discovery process started from warfarin, which is a weak HIV-1 protease inhibitor.
Dasatinib can be regarded as a pharmacological analogue of imatinib. Dasatinib is more potent and it can be used in imatinib-resistant cases for the treatment of chronic myelogenous leukemia (CML).
Lapatinib can be regarded as a pharmacological analogue of erlotinib. It is a tyrosine kinase inhibitor and was first approved for the treatment of solid tumors such as in breast cancer.
Venlafaxine is the first marketed serotonin/norepinephrine reuptake inhibitor (SNRI) and is used for the treatment of deep depression. Its active metabolite is desvenlafaxine, which has some advantageous properties; for example, it has a more favorable metabolic profile compared to venlafaxine.
Rilpivirine is a new HIV-1 nonnucleoside reverse transcriptase inhibitor (NNRTI), an analogue of etravirine. Rilpivirine is highly potent also against strains that are resistant to the first-generation NNRTI drugs.
The first volume of Analogue-Based Drug Discovery discussed mostly well-established drugs. This second volume also opens the door to new drug discoveries and the editors hope that, like the first volume, all of the drugs discussed in this book will have a bright future.
Abbreviations
ABC ATP binding cassette
ABDD analogue-based drug discovery
ABPM ambulatory blood pressure monitoring
ACAT acyl-CoA:cholesterol acyltransferase
ACE angiotensin-converting enzyme
ACTH adrenocorticotropic hormone
ADMET absorption, distribution, metabolism, excretion and toxicity
AFC 7-amino-4-trifluoromethylcoumarin
AIDS acquired immunodeficiency syndrome
ALT alanine aminotransferase
ALL acute lymphoblastic leukemia
AMP amprenavir
cAMP cyclic 3′,5′-adenosine monophosphate
ANDA Abbreviated New Drug Application
α-APA α-anilinophenylacetamide
APV amprenavir
AR androgen receptor
ATP adenosine triphosphate
AUC area under the curve
AZT azidothymidine
BBB blood-brain-barrier
Bcr-Abl Breakpoint cluster region - Abelson
BG blood glucose
b.i.d. twice a day (from Latin bis in die)
BOC t-butoxycarbonyl
CBF cerebral blood flow
CC50 50% cytotoxic concentration
β-CCE ethyl β-carboline-3-carboxylate
CGI Clinical Global Impressions Scale
CHB chronic hepatitis B
CK creatine kinase
CL clearance
CLR renal clearance
CLT total clearance
CLV clevudine
CLV-TP clevudine triphosphate
CML chronic myelogenogenous leukemia
CMRglc cerebral metabolic rate of glucose
CNS central nervous system
COBP chronic obstructive broncho-pneumopathies
COPD chronic obstructive pulmonary disease
COX-1 cyclooxygenase-1
COX-2 cyclooxygenase-2
CPI/r comparator protease inhibitor boosted with ritonavir
CPT camptothecin
CRC colorectal cancer
CYP cytochrome P450 isoenzyme
DA dopamine
10-DAB 10-deacetyl-baccatin
DAPY diarylpyrimidine
DATA diaryltriazine
dCK deoxycytidine kinase
DNA desoxyribonucleic acid
cDNA complementary deoxyribonucleic acid
cccDNA covalently closed circular DNA
mtDNA mitochondrial DNA
DOC deoxycorticosterone
DOCA deoxycorticosterone acetate
DPP-4 dipeptidyl peptidase 4
DSM-III Diagnostic and Statistical Manual of Mental Disorders, third edition
EBV Epstein-Barr virus
EC50 effective concentration 50
ED erectile dysfunction
EFS electric field stimulation
EGFR epidermal growth factor receptor
EMEA European Medicines Agency
EPA Environmental Protection Agency
EPO European Patent Office
EPS exprapyramidal side effect
Erk extracellularly regulated kinase
ETC emtricitabine
FAAH fatty acid amide hydrolase
FBDD fragment-based drug design
FDA Food and Drug Administration
L-FEAU 1-(2′-deoxy-2′-fluoro-β-L-arabinofuranosyl)-5-ethyluridine
FEV forced expiratory volume
L-FMAU L-2′-fluoro-5-methyl-β-L-arabinofuranosyluracil
GABAA gamma-aminobutyric acid A
GAD generalized anxiety disorder
GI growth inhibition
GIP glucose-dependent insulinotropic polypeptide
GLP-1 glucagon-like peptide-1
cGMP cyclic 3′,5′-guanosine monophosphate
GPIIb/IIIa glycoprotein IIb/IIIa
HA heavy atom
HAART Highly Active Antiretroviral Therapy
HA/ACTH histamine-induced adrenocorticotropic hormone
HAM-A Hamilton Anxiety Taring Scale
HAM-D Hamilton Depression Rating Scale
HbA1c glycosylated haemoglobin
HBV hepatitis B virus
HBcAg hepatitis B core antigen
HBeAg hepatitis B e antigen
HbsAg hepatitis B surface antigen
HCC hepatocellular carcinoma
HCV hepatitis C virus
HDV hepatitis delta virus
hERG human ether-a-go-go-related gene
HFB human foreskin fibroblast
HIAA 5-hydroxy-indole acetic acid
HIV human immunodeficiency virus
HIV PR HIV protease
HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
5-HT 5-hydroxytryptamine (serotonin)
5-HTP 5-hydroxytryptophan
HTS high-throughput screening
IBMX isobutylmethylxanthine
IC50 inhibitory concentration 50
pIC50 −log IC50
ICS inhaled corticosteroids
IDR idarubicin
IDV indinavir
i.m. intramuscular
IND Investigational New Drug
INN International Nonproprietary Name
IOPY iodophenoxypyridone
i.p. intraperitoneal
i.v. intravenous
Ki inhibitory constant
LABA long-acting β2-agonist
Lck lymphocyte specific kinase
hLck human Lck
mLck murine Lck
LDL-C low-density lipoprotein-cholesterol
LE ligand efficiency
LPV lopinavir
LVEF left ventricular ejection fraction
MADRS Montgomery-Asberg Depression Rating Scale
MAOI monoamine oxidase inhibitor
M1 muscarinic receptor M1 subtype
MAP mitogen-activated protein
rMD restrained molecular dynamics
MDD major depressive disorder
MDR multidrug resistance
MED minimal effective dose
MES maximal electroshock seizure
MIC minimal inhibitory concentration
MR mineralocorticoid receptor
MRP multidrug resistance-associated protein
MTD maximum tolerated dose
NAPQI N-acetyl-p-benzoquinone imine
NCE New Chemical Entity
NCI National Cancer Institute
NDA New Drug Application
NE norepinephrine
NMR nuclear magnetic resonance
NNRTI nonnucleoside reverse transcriptase inhibitor
NO nitric oxide
NPs natural products
NPC1L1 Niemann-Pick C1-Like-1
NRIs norepinephrine reuptake inhibitors
NRTI nucleoside reverse transcriptase inhibitor
NSAIDs nonsteroidal anti-inflammatory drugs
NSCLC non-small cell lung cancer
OADs oral antidiabetic drugs
OC ovarian cancer
OCD obsessive-compulsive disorder
OGTT oral glucose tolerance test
PCA p-chloroamphetamine
PCF plant cell fermentation
PCT Patent Cooperation Treaty
PDEs phosphodiesterases
PDGFR platelet derived growth factor receptor
PEP prolyl endopeptidase
PGE1 prostaglandin E1
PGE2 prostaglandin E2
P-gp permeability glyocoprotein
Ph (+) Philadelphia chromosome positive
PK pharmakokinetic
PKG protein kinase G
POMS profile of mood state
PPCE postproline cleaving enzyme
PR progesterone receptor
QSAR quantitative structure-activity relationship
q.d. or QD once a day (from Latin quaque die)
RBA relative binding affinity
RGD arginine-glycine-aspartic acid
RNA ribonucleic acid
RNApol RNA polymerase
mRNA messenger RNA
RT reverse transcriptase
RTV ritonavir
SAR structure-activity relationship
SBDD structure-based drug design
s.c. subcutaneous
SCID severe combined immunodeficient
SCLC small-cell lung cancer
SEDDS self-emulsifying drug delivery system
SEF sodium excreting factor
SI selectivity index
SIV simian immunodeficiency virus
SMC smooth muscle cell
SNRI serotonin/norepinephrine reuptake inhibitor
SQV saquinavir
Src sarcoma
SRI serotonin reuptake inhibitor
SSRIs selective serotonin reuptake inhibitors
TCR T-cell antigen receptor
TDF tenofovir disoproxil fumarate
TGFα tansforming growth factor-α
TI tumor inhibition
TIBO 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk]benzodiazepin-2(1H)-one
t.i.d. three times daily
TK thymidine kinase
TMPK thymidylate kinase
TPV tipranavir
TPV/r tipranavir/ritonavir combination
TPT topotecan
TRIPs Trade-related Aspects of Intellectual Property Rights
TTP time to progression
UDP uridine diphosphate
UGT uridine diphosphate glucuronyl transferase
USAN United States Adopted Names
VEGFR vascular endothelial growth factor receptor
VMS vasomotor symptoms
VSMC vascular smooth muscle cell
VSS steady-state volume
WBC white blood cell
WHcAg woodchick hepatitis virus core antigen
WHsAg woodchuck hepatitis virus surface antigen
WHV woodchuck hepatitis virus
WTO World Trade Organization