A SHORT PHARMACEUTIC CHEMISTRY: INORGANIC AND ORGANIC

By W. NADAO

CONTENTS CHAPTER 1 CELL SIGNALING AND DISEASES INTRODUCTION 1 1 1 COMPONENTS OF CELL-SIGNALING PATHWAYS CHEMICAL MESSENGERS 1 2 1 FIRST MESSENGERS (SIGNALING MOLECULES) 1 2 2 SECOND MESSENGERS SIGNAL TRANSDUCTION 1 3 1 SIGNAL TRANSDUCTION ENZYME EFFECTORS SIGNAL TRANSDUCTION MODULATORS AS DRUGS INTERCELLULAR (BETWEEN-CELLS) SIGNALING 1 6 1 FLUID COMPARTMENT 1 6 2 EXTRACELLULAR MATRIX 1 6 3 TYPES OF INTERCELLULAR SIGNALING (COMMUNICATION) BETWEEN CELLS HOMEOSTASIS REGULATED BY SIGNALING PATHWAYS SIGNALING IN CELLULAR METABOLISM 1 8 1 METABOLIC PATHWAY 1 8 2 METABOLITES 1 8 3 METABOLOMICS DISEASES 1 9 1 MAIN CAUSES OF DISEASES 1 9 2 CLASSIFI CATION OF DISEASES 1 9 3 ADDITIONAL DISEASE CONCEPTS UNDERSTANDING SIGNALING PATHWAYS IN THE PATHOGENESIS OF DISEASES UNEXPLORED AND EMERGING INTRACELLULAR SIGNALING COMPONENTS AS THERAPEUTIC TARGETS 1 11 1 PEROXISOMES 1 11 2 LYSOSOMES 1 11 3 AUTOPHAGY 1 11 4 PROTEASOMES HISTORY OF DRUG RESEARCH 1 12 1 CLASSIFICATION OF DRUGS BASED ON THEIR ACTION ON SIGNALING PATHWAYS EXERCISES COMPETITIVE EXAM QUESTIONS REFERENCES CHAPTER 2 AN OVERVIEW OF DRUG ACTION DEFINITION OF DRUGS TYPES OF PHARMACOLOGICAL ACTION OF THE DRUGS (THEORIES OF DRUG ACTIVITY) 2 2 1 STRUCTURALLY NONSPECIFIC DRUGS 2 2 2 STRUCTURALLY SPECIFIC DRUGS 2 2 3 DRUGS THAT DON’T ACT ON RECEPTORS CLASSIFICATION OF DRUGS BASED ON THEIR ORIGIN 2 3 1 NATURALLY OCCURRING COMPOUNDS AS DRUGS 2 3 2 SYNTHETIC COMPOUNDS DRUG ACTION 2 4 1 ABSORPTION (A) 2 4 2 DISTRIBUTION (D) 2 4 3 METABOLISM 2 4 4 EXCRETION 2 4 5 TOXICITY FACTORS AFFECTING ADMET 2 5 1 PHYSICOCHEMICAL PARAMETERS OF DRUGS 2 5 2 PHYSIOLOGICAL FACTORS CHAPTER 3 THE MODERN DRUG DEVELOPMENT PROCESS THE MODERN DRUG DEVELOPMENT PROCESS COMPRISES FIVE STEPS 3 2 1 DRUG DISCOVERY AND DEVELOPMENT 3 2 2 PRECLINICAL RESEARCH 3 2 3 CLINICAL TRIALS 3 2 4 FDA REVIEW 3 2 5 FDA MONITORING INITIAL STEPS IN DRUG DISCOVERY PROCESS (MEDICINAL CHEMISTRY) 3 3 1 GENERATION OF LIBRARY OF CHEMICAL COMPOUNDS 3 3 2 SCREENING OF CHEMICAL LIBRARIES IN VIVO SCREENING ASSAYS SCREENING IN MODEL ORGANISMS (OUR DISTANT FAST BREEDING COUSINS) 3 5 1 DANIO RERIO (ZEBRAFISH) 3 5 2 CAENORHABDITIS ELEGANS 3 5 3 DROSOPHILA MELANOGASTER CHAPTER 4 STRATEGIES FOR IDENTIFYING HIT MOLECULES HIT MOLECULES 4 1 1 RANDOM IN VITRO HIGH-THROUGHPUT SCREENING OF CHEMICAL LIBRARIES AGAINST BIOLOGICAL TARGETS/WHOLE CELLS 4 1 2 IN VITRO HIGH THROUGHPUT SCREENING OF FOCUSED CHEMICAL LIBRARIES AGAINST A VALIDATED BIOLOGICAL TARGETS OR WHOLE CELLS 4 1 3 CHARACTERISTICS OF HITS 4 1 4 STRATEGIES FOR IDENTIFYING HITS LEADING TO DRUG CANDIDATES 4 1 5 SOURCES FOR HITS SERENDIPITY IN DRUG DISCOVERY 4 2 1 CHLORPROMAZINE 4 2 2 MINOXIDIL 4 2 3 ASPARTAME 4 2 4 VIAGRA (SILDENAFIL CITRATE) 4 2 5 WARFARIN 4 2 6 CNS DRUGS ENDOGENOUS SOURCES (DERIVED FROM HUMANS OR ANIMALS) FOR THE IDENTIFICATION OF DRUG CANDIDATE(S) 4 3 1 ENDOCRINE HORMONES AND THEIR THERAPEUTIC APPLICATIONS 4 3 2 STEROID HORMONES AS ENDOGENOUS SOURCE FOR DRUGS 4 3 3 PEPTIDE/PROTEIN ENDOCRINE HORMONES AS ENDOGENOUS SOURCE FOR DRUGS MONOCLONAL ANTIBODY THERAPY 4 4 1 MONOCLONAL ANTIBODIES IN DIAGNOSTICS 4 4 2 TREATING DISEASE AT THE RNA LEVEL WITH OLIGONUCLEOTIDES DRUGS OF MICROBIAL ORIGIN 4 5 1 DRUGS ISOLATED FROM ACTINOMYCETES 4 5 2 DRUGS ISOLATED FROM FUNGI 4 5 3 DRUGS ISOLATED FROM BACTERIA TRADITIONAL METHODS AS A SOURCE FOR HIT IDENTIFICATION (EXOGENOUS SOURCES) 4 6 1 PACLITAXEL (TAXOL) TARGET-BASED SCREENING AS A RATIONALIZED APPROACH FOR THE IDENTIFICATION OF HIT/LEAD MOLECULES 4 7 1 QUALITY OF CHEMICAL LIBRARIES 4 7 2 FRAGMENT-BASED DRUG DISCOVERY FOR IDENTIFYING HITS 4 7 3 VIRTUAL SCREENING FOR IDENTIFYING HITS 4 7 4 PHENOTYPIC SCREENING FOR IDENTIFYING HITS 4 7 5 REPOSITIONING OF DRUGS FOR IDENTIFYING HITS DIFFERENCE BETWEEN FRAGMENTS, HITS, AND LEADS CHAPTER 5 DRUG DESIGN STRATEGIES HIT TO LEAD 5 2 1 CHARACTERISTICS OF LEAD MOLECULES CHARACTERISTICS OF PRECLINICAL CANDIDATES LEAD OPTIMIZATION/DRUG DESIGN STRATEGIES 5 4 1 PHARMACOPHORE IDENTIFICATION 5 4 2 EXTENSIVE STRUCTURE ACTIVITY RELATIONSHIP TO IMPROVE POTENCY AND SELECTIVITY 5 4 3 FUNCTIONAL GROUP MODIFICATION 5 4 4 STRUCTURAL MODIFICATIONS TO INCREASE THE ACTIVITY 5 4 5 STRUCTURE-BASED DRUG DESIGN 5 4 6 BIOISOSTERISM AND DRUG DESIGN 5 4 7 STEREOISOMERISM IN DRUG DESIGN 5 4 8 DRUG DESIGN STRATEGIES TO IMPROVE ABSORPTION VIA MODULATING POLARITY 5 4 9 PREVENTING DEGRADATION OF DRUGS (DRUG STABILITY) 5 4 10 DRUG DESIGN STRATEGIES USED FOR TARGETING DRUGS 5 4 11 PRODRUG STRATEGY 5 4 12 STRUCTURE–PROPERTY RELATIONSHIP 5 4 13 ALLOSTERIC MODULATORS AS AN EMERGING CONCEPT IN DRUG DESIGN 5 4 14 ‘ME TOO’ STRATEGIES FOR DRUG DESIGN 5 4 15 ANTIMETABOLITE STRATEGY FOR DRUG DESIGN 5 4 16 ROLE OF DMPK FOR THE SELECTION OF PRECLINICAL CANDIDATE TIMELINE OF A PHARMACEUTICAL DRUG DEVELOPMENT FROM LABORATORY TO CLINICS CHAPTER 6 ROLE OF PHYSICOCHEMICAL PROPERTIES OF CHEMICAL STRUCTURES IN DRUG DESIGN LIPINSKI’S RULE OF FIVE 6 2 1 THE RULE OF THREE (RO3) IONIZATION CONSTANT (PKA ) 6 3 1 IONIZATION OF BASE 6 3 2 IONIZATION OF ACID 6 3 3 ROLE OF PKA IN ADMET AND TARGET-BINDING 6 3 4 STRENGTH OF ACIDIC/BASIC COMPOUNDS IN PERIODIC TABLE SOLUBILITY OF DRUGS LIPOPHILICITY 6 5 1 EFFECT OF PKA ON LIPOPHILICITY 6 5 2 EFFECT OF LIPOPHILICITY ON SOME OF THE PK/PD PARAMETERS IN VITRO 6 5 3 APPARENT PERMEATION COEFFICIENT (PAPP ) 6 5 4 DISTRIBUTION COEFFICIENT (LOGD) 6 5 5 LIPOPHILIC EFFICIENCY 6 5 6 EFFECT OF LIPOPHILICITY ON LOCAL ANESTHETICS 6 5 7 EFFECT OF PKA ON LOCAL ANESTHETICS HYDROGEN BOND ACCEPTOR (HBA)/HYDROGEN BOND DONOR (HBD) SURFACE ACTIVITY 6 7 1 APPLICATIONS NUMBER OF ROTATABLE BONDS NUMBER OF AROMATIC RINGS UNDESIRABLE FUNCTIONAL GROUPS (ALERT) STERIC FACTOR MOLECULAR SIZE 6 12 1 MOLECULAR WEIGHT 6 12 2 ELECTRON DENSITY 6 12 3 POLAR SURFACE ACTIVITY PHYSICOCHEMICAL PROPERTIES OF A SUCCESSFUL CNS DRUG PHYSICOCHEMICAL PARAMETERS REQUIRED FOR A PRECLINICAL CANDIDATE DRUG CHAPTER 7 RECEPTOROLOGY RECEPTORS AS DRUG TARGET 7 2 1 COMPARISON BETWEEN RECEPTORS AND ENZYMES 7 2 2 INTRAVITAL LIGANDS (ENDOGENOUS) 7 2 3 LIGANDS THAT ENTER CELLS 7 2 4 LIGANDS THAT DO NOT ENTER CELLS 7 2 5 SIGNAL TRANSDUCTION DISTRIBUTION OF RECEPTORS IN THE CELL 7 3 1 CELL-SURFACE RECEPTORS 7 3 2 ENZYME-LINKED RECEPTORS 7 3 3 IONOTROPIC RECEPTORS 7 3 4 INTRACELLULAR RECEPTORS (NUCLEAR RECEPTORS) CHAPTER 8 DRUG RECEPTOR THEORIES DRUG–RECEPTOR OCCUPATION THEORIES 8 1 1 HYPOTHESIS OF CLARK 8 1 2 HYPOTHESIS OF ARIENS AND STEPHENSON 8 1 3 SIMPLE OCCUPANCY THEORY 8 1 4 RATE THEORY 8 1 5 MACROMOLECULAR PERTURBATION THEORY 8 1 6 ACTIVATION AGGREGATION THEORY 8 1 7 THE RECEPTOR COOPERATIVITY MODEL 8 1 8 THE MOBILE RECEPTOR HYPOTHESIS 8 1 9 TWO-STATE RECEPTOR THEORY GENERAL MECHANISM OF DRUG–RECEPTOR INTERACTION 8 2 1 LOCK AND KEY HYPOTHESIS 8 2 2 INDUCED FIT MODEL DRUG–RECEPTOR COMPLEX FORMATION AND DISSOCIATION 8 3 1 THE DOSE–RESPONSE RELATIONSHIP 8 3 2 BINDING AFFINITY AND KD 8 3 3 RELATIONSHIP BETWEEN FORMATIONS OF DRUG–RECEPTOR COMPLEXES WITH OCCUPANCY OF RECEPTORS 8 3 4 CALCULATION OF RECEPTOR OCCUPANCY AGONISTS/PARTIAL AGONISTS/INVERSE AGONISTS 8 4 1 DRUG AGONISTS 8 4 2 PARTIAL AGONISTS 8 4 3 INVERSE AGONISTS SPARE RECEPTORS 8 5 1 EXAMPLES OF SPARE RECEPTORS CHAPTER 9 RECEPTOR ANTAGONISTS ORTHOSTERIC BINDING SITE ALLOSTERIC SITE 9 3 1 POSITIVE ALLOSTERIC MODULATORS (PAMS) 9 3 2 NEGATIVE ALLOSTERIC MODULATION (NAM) 9 3 3 SILENT ALLOSTERIC MODULATORS RECEPTOR ANTAGONISTS 9 4 1 ANTAGONISTS FOR CELL SURFACE RECEPTORS 9 4 2 ENZYME-LINKED RECEPTOR BLOCKERS 9 4 3 ION CHANNEL BLOCKERS (IONOTROPIC RECEPTOR ANTAGONISTS) 9 4 4 ANTAGONISTS FOR INTRACELLULAR NUCLEAR RECEPTOR 9 4 5 TYPES OF ANTAGONISM CHAPTER 10 DRUG–TARGET INTERACTIONS 10 1 1 STRUCTURAL FEATURES IN COMPOUNDS INVOLVED IN BINDING 10 1 2 STRUCTURE OF PROTEIN TARGETS 10 1 3 ROLE OF WATER IN DRUG-PROTEIN INTERACTION REVERSIBLE INTERACTION 10 2 1 HYDROGEN BONDS 10 2 2 IONIC BOND (SALT BRIDGE) 10 2 3 VAN DER WAALS FORCES 10 2 4 DIPOLE-DIPOLE/ION-DIPOLE/DIPOLE-DIPOLE INDUCED FORCES 10 2 5 HYDROPHOBIC INTERACTION IRREVERSIBLE DRUG-TARGET INTERACTION (COVALENT BONDS) SUMMARY OF DRUG-TARGET INTERACTIONS 10 4 1 WEAK INTERACTIONS DURING BINDING OF DRUG WITH GPCR CHAPTER 11 PHARMACOKINETICS 11 1 1 GASTROINTESTINAL REGION AS A PHYSIOLOGICAL BARRIER 11 1 2 LIVER AS A PHYSIOLOGICAL BARRIER 11 1 3 PHYSIOLOGICAL BARRIERS DURING BLOOD CIRCULATION 11 1 4 AQUEOUS/LIPID ENVIRONMENT AS A PHYSIOLOGICAL BARRIER 11 1 5 PH OF AQUEOUS ENVIRONMENT AS A PHYSIOLOGICAL BARRIER 11 1 6 EFFECT OF PHYSICOCHEMICAL PROPERTIES OF DRUGS/TEST COMPOUNDS ON ADME KINETICS OF ADME 11 2 1 ABSORPTION 11 2 2 DISTRIBUTION 11 2 3 METABOLISM 11 2 4 EXCRETION METHODS FOR ASSESSING MAJOR PHYSICOCHEMICAL PROPERTIES OF COMPOUNDS THAT AFFECT ADME PARAMETERS 11 3 1 MEASURING SOLUBILITY 11 3 2 MEASURING LIPOPHILICITY 11 3 3 MEASURING PKA 11 3 4 MEASURING PERMEABILITY SUMMARY OF IMPORTANT PK PARAMETERS CHAPTER 12 PHARMACODYNAMICS BIOCHEMISTRY OF ENZYMES 12 2 1 ENZYMES AS BIOCATALYSTS 12 2 2 ACTIVE SITE 12 2 3 COFACTORS 12 2 4 ENZYME-CATALYSED REACTIONS 12 2 5 ENZYME–SUBSTRATE COMPLEX 12 2 6 ENZYME-SUBSTRATE INTERACTIONS 12 2 7 FACTORS AFFECTING ENZYME ACTIVITY ALLOSTERIC ENZYMES 12 3 1 ALLOSTERIC ACTIVATION (PAM) 12 3 2 ALLOSTERIC INHIBITION (NAM) 12 3 3 SILENT ALLOSTERIC MODULATORS (SAM) 12 3 4 EFFECT OF ALLOSTERIC MODULATION ON REACTION KINETICS NOMENCLATURE OF ENZYMES 12 4 1 THE EC NUMBERS ROLE OF ENZYMES 12 5 1 DIAGNOSTIC ENZYMES 12 5 2 THERAPEUTIC USE OF ENZYMES 12 5 3 ENZYMES AS THERAPEUTIC TARGETS CHAPTER 13 ROLE OF ENZYMES IN METABOLISM 13 1 1 MICROSOMAL ENZYMES 13 1 2 NON-MICROSOMAL ENZYMES CYP-MEDIATED METABOLISM 13 2 1 TYPES OF METABOLIC REACTIONS EXAMPLES OF PHASE I AND II DRUG METABOLISM CYTOCHROME P450 ENZYME INDUCTION AND INHIBITION 13 4 1 ENZYME INDUCTION 13 4 2 ENZYME INHIBITION CYP ENZYME INDUCTION BY EXOGENOUS SUBSTANCES (PHARMACOKINETIC DRUG-DRUG INTERACTIONS) 13 5 1 PHYSIOLOGICAL CONSEQUENCES OF CYP ENZYME INDUCTION PHARMACODYNAMIC DRUG-DRUG INTERACTIONS DRUG-DESIGN APPROACH FOR MAKING DRUGS MORE RESISTANT TO CYP METABOLISM EXAMPLES OF OTHER NON-MICROSOMAL METABOLISMS CHAPTER 14 DIGESTIVE ENZYMES 14 1 1 RELEASE OF DIGESTIVE ENZYMES DIGESTION OF PROTEINS 14 2 1 PROTEASES ZYMOGENS (PROENZYMES) 14 3 1 PEPSINOGEN 14 3 2 PANCREATIC ZYMOGENS PROTEIN HOMEOSTASIS DIGESTION OF LIPIDS 14 5 1 EMULSIFICATION AND DIGESTION DIGESTION OF CARBOHYDRATES