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Medicinal chemistry unit1&3

This document provides an overview of the field of medicinal chemistry. It defines medicinal chemistry as an interdisciplinary research area that incorporates different branches of chemistry and biology to research and develop new drugs. The roles of medicinal chemists include synthesizing and characterizing new compounds, determining biological effects, optimizing lead compounds, and studying pharmacokinetic properties. It also discusses the drug development process and clinical trials. Key aspects covered include drug classification, sources of drug leads, and factors that influence drug properties such as stability and bioavailability.

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Medicinal Chemistry an Introduction Chapter I 1
2 Medicinal chemistry (IUPAC): “it concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level” In other words, Medicinal chemistry is an interdisciplinary research area incorporating different branches of chemistry and biology in the research for better and new drugs (Drug Discovery).
MEDICINAL CHEMISTRY Computational Chemistry Microbiology Pharmacology Combinatorial Chemistry X-ray crystallography Spectroscopy Immunology Organic Chemistry 3 Genomics/proteomics Molecular Modeling Pharmaceutics
Role of Medicinal Chemists • Synthesis and characterization of new compounds (leads). • Biological assay of the synthesized compounds and determine their effect on biological processes. • Manipulation of structure of the compound for optimum effect and minimum side effects (optimization of lead) • Study of pharmacokinetic and pharmacodynamic property of drug. • optimization of synthetic route for bulk production 4
5 Drug Vs Medicine
Drug Vs Medicine • There is no sharp demarcation to define Drug and medicine. • These are the chemical substances that are used to prevent or cure diseases in humans, animals and plants. • A compound during its studies in the drug development process, is better to called as Drug, whereas Medicine is actually that chemical species which after its approval from the concern authority and which is be prescribed. • Drug is also used by the media and the general public to describe the substances taken for their psychotic rather than medicinal effects. 6
Drugs Medicine Recreational Nootropics 7
Medicine • A medicine or medication is a substance taken to cure and/or improve any symptoms of an illness. OR • A medicine may be used as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. • Dispensing of medication is often regulated by governments into three categories: • Over-the-counter (OTC) • Prescription only medicines (POM) • Behind-the-counter (BTC) 8
• Over-the counter (OTC) : Drugs legally allowed to be sold, i.e. without the prescription of a registered medical practitioner. Vitamins and minerals, Cough and cold, Gastrointestinal, Analgesics /Dermatological. Aspirin, paracetamol. • Prescription only medicines (POM): Drugs which are not allowed to be sold without the prescription of a registered medical practitioner. E.g. antibiotics. • Behind-the counter (BTC): Drugs that are allowed to sold without prescription of RMP but also limits the bulk buying of such drugs. These products are accessed by patients only after discussion with the pharmacist and presenting proof of identification (ID). contraception pill Plan B (levonorgestrel) 9
• Substances that affect the CNS, and are or may be used for perceiving beneficial effects on perception, consciousness, personality, and behavior. E.g. Opioids (substance that bind the opioid receptors, e.g. morphine, codeine etc.) or hallucinogens (diphenhydramine). Recreational Drugs Cannabis Tetrahydrocannabinol (THC) 10
11 • Nootropics are drugs that are claimed to improve human cognitive abilities. They are used to improve memory, concentration, thought, mood, learning. Some are used to treat Parkinson's disease, and Alzheimer's disease. BESEB (“Bacosides Enriched Standardized Extract of Bacopa”) : Memory sure. Nootropics
no drug is completely safe • Beneficial and non-beneficial biological effects. • Drugs act by interfering with biological processes. • All drugs, including those non-prescription drugs such as aspirin and paracetamol. 12
• Beneficial and non-beneficial biological effects. • The unwanted effects are commonly referred to as side effects. • Side effects are not always non-beneficial. E.g. promethazine (antihistamine) Antihistamine, but also used as sedative or sleep aid 13
14 Drug resistance or tolerance (tachyphylaxis) • Repeated use of a drug - (increase in enzymes) • Downregulation of receptors - (break down of receptors) • Drug-resistant strains of microorganisms.
Drug discovery and design: a historical outline • 1910 - Paul Ehrlich and Sacachiro Hata - first rational approach – Arsphenamine - SAR • Chemotherapeutic index = Min. curative dose Max. tolerated dose Therapeutic index = LD50 ED50 TI: Measures of a drug’s beneficial effect at minimum dose Vs harmful effects at high dose 15
• 1905 - Langley – receptors, ligand, active conformation, pharmacophore • 1960 - Hansch & Fujita – QSAR 16
mid- to late twentieth century – knowledge of biological structures and processes local anaesthetic 17 antiarrhythmic
anticholinesterase •1970s and 1990s – molecular modeling and combinatorial chemistry 18
Current trends in Drug discovery** ** It’s all a team work 19
Drug Discovery Pipeline Lead discovery 20 Lead Optimization Candidate Selection Preclinical development Clinical development Marketing Hit Lead Preclinical Candidate Clinical Candidate NDA DRUG * takes 7-10 years to come to market with a new drug at costs ~ $ 150-800 million. ** extremely expensive test procedures required (preclinical and clinical tests)
Post-marketing surveillance: collection of adverse drug reaction data Regulatory Review: additional system that tracks long-term effects Development Research: Drug is given to an increasing number of individuals Phase III: 3000+ patients, half given drug under test, half given placebo Phase II: 200-400 patients receive the drug Phase I: 50-100 healthy volunteers Discovery research Identification of lead compounds: compds. shown to have biological activity Synthesis of analogues: many structurally related compounds are made and tested Biological evaluation of compounds: in vitro and in vivo testing. DRUG Drug development pyramid 21
Clinical trial A clinical trial (also called clinical research) is a research study using human volunteers designed to determine the safety and effectiveness of a drug, biologic (such as a vaccine), device (such as a prothesis) or other treatment or behavioral intervention. 22
23 • phase I : tests on healthy pharmacodynamics, toxicity). volunteers (pharmacokinetics, • phase II : tests on a limited number of persons with specific disease (efficacy). • phase III : global tests on broad clinical basis (definite safety, optimal dosage). • phase IV : registration, market support.
24 Outcome of Pharmaceutical research/ Drug Discovery • new products with enhanced activity • new products with diminished side effects • need of new products by increasing resistance • but on the other hand: • high development costs • unfavorable ratio between synthesized compounds and products on the market
Leads and analogues: desirable properties • Bioavailability – Lipinski’s rule of five. • Solubility – lipophilicity and hydrophilicity. • Structure – stereo electronic properties. E.g. anticancer drug melphalan, centchroman. N Cl ClNH2 Melphalan O HO O centchroman O O N 25
26
CH3 CH3 CH3 CH3 O O (R)-(+)- (S)-(-)- (S)-(+)- (R)-(-)- orange lemon caraway peppermint Biological effects of Enantiomers Limonene Carvone CHO OCH3 OH strong odor vanillin 27 CHO OH OCH3 no odor isovanillin
• Stability - after administration and self-life. drug’s in situ stability A. modifying its structure. B. administering the drug as a more stable prodrug. C. using a suitable dosage form. treatment of glaucoma lasts for about three hours, needs 3–6 doses a day 28
Drug stability by complex formation Prodrug stability • Self-life Self-life is the time taken for a drug’s pharmacological activity to decline to an unacceptable level. --- microbial degradation and adverse chemical reactions 29
Sources of leads and drugs • Originally drugs and leads were derived from natural sources Now- • Local folk remedies (Ethnopharmacology). • by serendipitously discovered (penicillin, Minoxidil, cisplatin etc.) • by structure-activity relationships (most) • by rational drug design (since the 80‘s) • High-throughput screening of compounds (since the 90‘s) • Databases and other literature sources of organic compounds. 30
Ethnopharmaceutical sources: • Quinine from cinchona bark - Antimalarial • Reserpine isolated from Rauwolfia serpentina – Antidepressant • Digitalis purpurea - digitoxigenin, gitoxigenin – Congestive heart failure. * Cardenolides: having an α,β unsaturated γ lactone ring. Or butyrolactone ring. Eg. digitoxin, digitoxigenin, digoxin, etc * Bufadienolides/Scilladienolides: containing a δ ring having a conjugated diene system. Or -pyrone ring eg. Bufotalin. 31
• Plant sources – Taxol Taxus breifolia Vincirstine Vinca rosea Linn Morphine opium poppy Compounds with antifungal activity isolated from fungus resistant African plants • Animal sources – adrenaline and insulin 32
• Marine sources – Avarol an immunodeficiency virus inhibitor. sponge Disidea avara Ara-A antiviral sponge T ethya crypta. cephalosporin C fungus Acremonium chrysogenium • Micro organism source – Benzylpenicillin (penicillin G) Penicillin notatum Streptomycin Streptomyces griseus 33
Classification of drugs • Drugs are classified in different ways depending on where and how the drugs are being used. • On the basis of Pharmacological Activity • On the basis of chemical structure • On the basis of origin (Natural, synthetic, semi-synthetic, biosynthetic) 34
35 This classification lists drugs according to the nature of their pharmacodynamic behavior. Pharmacological Activity • Analgesics: Analgesics are the class of compounds that relieve pain. The all sort of pains such as headaches, backaches, joint pain etc., and pain that result from surgery, injury or illness. Among the most common Analgesics are Aspirin, Choline Salicylate, Magnesium Salicylate and Sodium Salicylate
• Non-steroidal Anti-inflammatory Drugs (NSAIDs) : relieve pain, swelling, stiffness, and inflammation. NSAIDs are prescribed for a variety of painful conditions, including Arthritis, Gout, sprains, strains, and other injuries. Non-steroidal Anti-inflammatory Drugs relieve pain, stiffness, swelling, and inflammation, but they do not cure the diseases or injuries responsible for these problems. Ibuprofen, Naproxen Sodium and Ketoprofen are Non-Steroidal Anti- Inflammatory Drugs (NSAIDs). NSAIDs relieve pain and also reduce inflammation. Another common analgesic, Acetaminophen provides pain relief but does not reduce inflammation. COOH NHCOCH3 COOH OCOCH3 OH Ibuprofen 36 ParacetamolAsprin
Vasodilators : Vasodilators are substances that act directly on muscles in blood vessel walls to make blood vessels widen (dilate). Vasodilators are used to treat high blood pressure (hypertension). By widening the arteries, these drugs allow blood to flow through more easily, reducing blood pressure. Diuretics : Substances that increases the removal of fluids from the body. Diuretics are used for many reasons. They may be indicated for people who suffer from edema, an intense accumulation of fluids in the body's tissues, and those who suffer from high blood pressure or other heart related diseases. Hypnotic : drugs are a class of psychoactive drugs whose primary function is to induce sleep and to be used in the treatment surgical anesthesia. Benzodiazepines, Nonbenzodiazepines 37
38 • Antiseptics: Antiseptics are substances that slow or stop the growth of germs and help prevent infections in minor cuts, scrapes, and burns. Antiseptics are applied to the skin to keep bacteria from getting into wounds and causing infection. Although Antiseptics do not usually kill bacteria, they do weaken them and slow their growth.
Chemical structure • Classification by means of chemical structure is useful to medicinal chemists who are concerned with synthesis and structure–activity relationships. 39
• Sulphonamides: are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positve and many gram- negative organisms. NH2 NH2 COOH PABA Involved in synthesis of DHFA, THFA and folate co-factor SO2NHR sulphonamide inhibit the synthesis of DHFA, THFA and folate co-factor N NO2 H S NH2N Sulphadiazine O2 H2N S NHCOCH3 Sulphacetamide O2 SH2N NH2 Dapsone 40
• Quinolones: These class of compounds constitutes a large numbers of synthetic antimicrobials agents that are highly effective in the treatment of many types of infectious disease, particularly those caused by bacteria. N R5 O COOHF R7 N O COOHF N ON H3C CH3 R8 R1 Fluoroquinolones R1 R5 R7 R8 Norfloxacin Ciprofloxacin Ofloxacin C2H5 NHNH H NHNH H C8 O CH3 NNH 41 1,8 Bridge Ofloxacin
On the basis of origin Natural : Plants- Animals- Microorganisms- and Minerals- Synthetic : Semi-Synthetic : Biosynthetic : human insulin, interferon, vaccines 42
N S O OH H N O O O Phenoxymethylpenicillin N S O penicillin OH H N O O R H H S PCl H N S N Semi-Synthetic N S O OH N O O TMSCl N S O Pyridine OTMS O O PCl5 N O BuOH OTMS O Cl N S O OTMS N O BuO N S O 6-APA OTMS H2N O H3O 43 + penicillium
O O O O H O H CH3 H CH3 H3C NaBH4 H3C Methanol O O H O O CH3 H CH3 H OH O O H O O CH3 CH3 H H3C OMe H MeOH, HCl Artemether O O O O H H Artemisinin CH3 44 H CH3 H3C OMe Artether EtOH, HCl
45 Physiological classification World Health Organization (WHO) 1. Agents acting on the central nervous system (CNS). psychotropic drugs neurological drugs 2. Pharmacodynamic agents. 3. Chemotherapeutic agents. 4. Miscellaneous agents.
Methods and routes of administration • parenteral or enteral : Parenteral routes are those which avoid the gastrointestinal tract (GI tract) • intramuscular injection (IM). • intravenous injection (IV) • subcutaneous injection (SC) • transdermal delivery systems • Nasal sprays and inhalers are also parenteral routes. • The enteral route is where drugs are absorbed from the alimentary canal (given orally, PO), rectal and sublingual routes. 46
The different methods of administering drugs 47 Method of Administration Anatomical Entryway Description / Efficiency Examples Oral taken by mouth Slow very convenient. Rate of absorption into the bloodstream from the stomach is low. Absorption occurs mostly in the small intestine tablets, pills, liquids Inhalation vapour breathed in Fast Passes directly to the bloodstream via the lungs respiratory medications for asthma Rectal (suppositories) insertion into the rectum Moderately-Fast absorption from the large intestine to the bloodstream digestive illness treatments, hemorrhoids Intravenous injection into vein Fastest precise amounts can be administered and absorption into the blood is fastest of all methods local anesthetics
48 Intramuscular injection into muscle Slowest relatively safe; therefore, larger amounts of the drug may be administered vaccines Subcutaneous injection directly into fat under the skin Medium Speed work best when administered in a constant area, especially in the thigh, upper arm, or waist dental injections Other: skin patches; eye or ear drops placed on skin; liquid given directly Varies skin patch: absorption from the skin into the blood eye/ear drops: liquid delivered directly often targets a single central area, usually that of infection hormone treatment; infection treatment nicotine patches
49
50
• The dose of a drug administered to a patient is the amount that is required to reach and maintain the concentration necessary to produce a favourable response at the site of biological action. Too high a dose usually causes unacceptable side effects, whilst too low a dose results in a failure of the therapy. • The limits between which the drug is an effective therapeutic agent is known as its therapeutic window. • The amount of a drug the plasma can contain, coupled with elimination processes that irreversibly remove the drug from its site of action, results in the drug concentration reaching a so-called plateau value. A simulation of a therapeutic window for a drug, given in fixed doses at fixed time intervals (") 51
52 • The dose of a drug and how it is administered is called the drug regimen. Drug regimens may vary from a single dose taken to relieve a headache, regular daily doses taken to counteract the effects of epilepsy and diabetes, to continuous intravenous infusions for seriously ill patients. Regimens are designed to maintain the concentration of the drug within the therapeutic window at the site of action for the period of time that is required for therapeutic success.
Introduction to Drug Design and Action Chapter II 53
54 Drug Design - To minimize the trial and error approach. Requires a detailed study of Pharmacodynamics.
55 Drug Action The action of a drug is believed to be due to the interaction of that drug with enzymes, receptors and other molecules found in the body.
56 Mode of Drug action • Killing foreign organisms: the action of chemotherapeutics. • Stimulation and depression: the action of SERMS • Irritation: irritant action on gastrointestinal tract. • Replacement: Insulin is used in diabetes
57 Sites of Drug action – Enzyme : Drug-Receptor Interaction : Non-Specific Interaction : Antacids
58 Drug-Receptor Interaction : Ionic interaction Dipole-dipole interaction Hydrogen bonding Hydrophobic interaction Van der Waal forces Covalent interaction Charge transfer interaction
Drug-Receptor Interaction 59
Binding of ester-type local anesthetic agents to a receptor site 60
Ionic Interactions - Strong electrostatic Interactions (5-10 kcal/mol) - Responsible for relative orientation of the drug to its binding site H N S O O- N O O + H3N HN O 61
Hydrogen Bonding Interactions (non-ionic/neutral) - Non-covalent bonds - Bond strength is distance dependent - Distance between the heteroatoms is about 2.2-3.5 Å N H N His, Try N H O H O O H H O 62
Hydrophobic/lipophilic Interactions - Most important interactions under physiological conditions - Come into play at closer distance than Ionic interactions - Binding of hydrophobic regions of a ligand in a hydrophobi pocket results in gain in entropy - Important role in many properties: Drug formulation, distribution etc. O N N 63
(a) hydrophobic bonding and (b) London dispersive forces 64
B B B B B B B B Drug residue DNA Chain DNA Chain B B BH2 H2B H2B BH2 HB BH Drug Covalent bond formation Base Intrastrand cross-link Intrastrand cross linking through covalent bonds 65 E.g. action of Nitrogen mustard.
H N N N H N E.g. N S CN Anticancer compound 41 Shaikh et al. Bioorg. Med. Chem. Lett. 2006, 16, 5917 66
Drug-Receptor interactions Receptor surface model with hydrophobic regions mapped on it. Hydrophobic regions are shown in brown and hydrophilic regions are shown in white. Compound 41 is placed within the generated receptor surface. Receptor surface model with hydrogen bonding propensity mapped on it. Hydrogen bond donor regions are shown in purple, while hydrogen bond acceptor regions are shown in cyan color. Compound 41 is placed within the generated receptor surface. 67
N H N S NH N 41 Docked conformation of compound 41 (grey) in the binding site. All the hydrogen atoms of the protein are removed for clarity. Hydrogen bonds are shown with dotted red lines. N N 68
69 • Receptor: Receptors are specific areas of certain proteins that are found either embedded in cellular membranes or in the nuclei of living cells which serve to recognize the endogenous or exogenous (drug) molecule and initiate response to it.
The fluid mosaic model of membranes 70
signal transduction. Effects of ligands binding to receptors 71
Receptors types 72
73 Drug action • Pharmacokinetic phase: The study of the parameters that control the journey of the drug from its point of administration to its point of action. • Pharmacodynamic phase: the chemical nature of the relationship between the drug and its target, in other words, the effect of the drug on the body.
74 The Pharmacokinetic phase (ADME) what the body does to the drug…
Absorption...The passage of the drug from its site of administration into the general circulatory system after enteral administration. • Filtration: (Most pores have a diameter of 0.6–0.7 nm, which allows the passage of species with relative molecular masses up to about 100) • Passive diffusion : along the concentration gradient. 75
• Facilitated diffusion : It involves specific carrier proteins known as permeases. It only occurs in the direction of the concentration gradient. • Active transport: It also involves carrier proteins but the movement is against the concentration gradient. 76
77 • the pH of the medium from which absorption occurs. • the drug’s partition coefficient. • the drug’s dosage form. • the drug’s particle size. • for orally administered drugs, in either solid or emulsion form, their rate of dissolution. Absorption depends on…
78 Distribution…It is the transport of the drug from its initial point of administration or absorption to its site of action. • In form of solution of drug molecules or bound to the serum proteins, usually albumins. Drug = Drug-Serum Protein complex • In designing drug regimens. • Drugs with poor water solubility to reach their target site. • The drug–protein complex acts as a depot. • Protein binding can also increase the duration of action
• Major factors that influence distribution are the solubility and stability of drugs in the biological environment of the blood. • … Concept of prodrug. • The distribution pattern of a drug through the tissues forming the blood vessels will depend largely on the nature of the tissue. 79
• Influence of drug’s lipophilicity in its distribution. 99.6% 98.5% polar endogenous compounds such as amino acids, sugars, nucleosides and small ions (Na+, Li+, Ca2+ and K+) are also able to cross the BBB. 80
Metabolism…Drug metabolism is the biotransformation of the drug into other compounds (metabolites) that are usually more water soluble than their parent drug and are usually excreted in the urine. • These biotransformations occur mainly in the liver but they can also occur in blood and other organs such as the brain, lungs and kidneys. • … Concept of prodrug 81
82
Excretion... Excretion is the process by which unwanted substances are removed from the body. • The main excretion route for drugs and their metabolites is through the kidney in solution in the urine And via bowel in the faeces. • …case of thalidomide S-Thalidomide Teratogenic 83 R-Thalidomide Sedative
• Prodrugs... Prodrugs are compounds that are pharmacologically inert but converted by enzyme or chemical action to the active form of the drug at or near their target site. E.g. levodopa, used to treat Parkinson’s syndrome, is the prodrug for the neurotransmitter dopamine. Dopamine is too polar to cross the blood–brain barrier but there is a transport system for amino acids such as levodopa. Once the prodrug enters the brain it is decarboxylated to the active drug dopamine 84
anti-inflammatory agent 85
86 The pharmacodynamic phase what the drug does to the body…
87 • PD is determined by the stereoelectronic property of the drug. • The stereoelectronic structure should be complementary to that of the target site. • The binding may have stimulating or inhibiting activity. • The bonding is due to weak electrostatic bonds such as hydrogen bond and van der Waals’ forces. • Or Permanent binding due to covalent bonds.
88 Drug Response curves

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Medicinal chemistry unit1&3

  • 1.
  • 2.
    2 Medicinal chemistry (IUPAC):“it concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level” In other words, Medicinal chemistry is an interdisciplinary research area incorporating different branches of chemistry and biology in the research for better and new drugs (Drug Discovery).
  • 3.
  • 4.
    Role of MedicinalChemists • Synthesis and characterization of new compounds (leads). • Biological assay of the synthesized compounds and determine their effect on biological processes. • Manipulation of structure of the compound for optimum effect and minimum side effects (optimization of lead) • Study of pharmacokinetic and pharmacodynamic property of drug. • optimization of synthetic route for bulk production 4
  • 5.
  • 6.
    Drug Vs Medicine •There is no sharp demarcation to define Drug and medicine. • These are the chemical substances that are used to prevent or cure diseases in humans, animals and plants. • A compound during its studies in the drug development process, is better to called as Drug, whereas Medicine is actually that chemical species which after its approval from the concern authority and which is be prescribed. • Drug is also used by the media and the general public to describe the substances taken for their psychotic rather than medicinal effects. 6
  • 7.
  • 8.
    Medicine • A medicineor medication is a substance taken to cure and/or improve any symptoms of an illness. OR • A medicine may be used as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. • Dispensing of medication is often regulated by governments into three categories: • Over-the-counter (OTC) • Prescription only medicines (POM) • Behind-the-counter (BTC) 8
  • 9.
    • Over-the counter(OTC) : Drugs legally allowed to be sold, i.e. without the prescription of a registered medical practitioner. Vitamins and minerals, Cough and cold, Gastrointestinal, Analgesics /Dermatological. Aspirin, paracetamol. • Prescription only medicines (POM): Drugs which are not allowed to be sold without the prescription of a registered medical practitioner. E.g. antibiotics. • Behind-the counter (BTC): Drugs that are allowed to sold without prescription of RMP but also limits the bulk buying of such drugs. These products are accessed by patients only after discussion with the pharmacist and presenting proof of identification (ID). contraception pill Plan B (levonorgestrel) 9
  • 10.
    • Substances thataffect the CNS, and are or may be used for perceiving beneficial effects on perception, consciousness, personality, and behavior. E.g. Opioids (substance that bind the opioid receptors, e.g. morphine, codeine etc.) or hallucinogens (diphenhydramine). Recreational Drugs Cannabis Tetrahydrocannabinol (THC) 10
  • 11.
    11 • Nootropics aredrugs that are claimed to improve human cognitive abilities. They are used to improve memory, concentration, thought, mood, learning. Some are used to treat Parkinson's disease, and Alzheimer's disease. BESEB (“Bacosides Enriched Standardized Extract of Bacopa”) : Memory sure. Nootropics
  • 12.
    no drug iscompletely safe • Beneficial and non-beneficial biological effects. • Drugs act by interfering with biological processes. • All drugs, including those non-prescription drugs such as aspirin and paracetamol. 12
  • 13.
    • Beneficial andnon-beneficial biological effects. • The unwanted effects are commonly referred to as side effects. • Side effects are not always non-beneficial. E.g. promethazine (antihistamine) Antihistamine, but also used as sedative or sleep aid 13
  • 14.
    14 Drug resistance ortolerance (tachyphylaxis) • Repeated use of a drug - (increase in enzymes) • Downregulation of receptors - (break down of receptors) • Drug-resistant strains of microorganisms.
  • 15.
    Drug discovery anddesign: a historical outline • 1910 - Paul Ehrlich and Sacachiro Hata - first rational approach – Arsphenamine - SAR • Chemotherapeutic index = Min. curative dose Max. tolerated dose Therapeutic index = LD50 ED50 TI: Measures of a drug’s beneficial effect at minimum dose Vs harmful effects at high dose 15
  • 16.
    • 1905 -Langley – receptors, ligand, active conformation, pharmacophore • 1960 - Hansch & Fujita – QSAR 16
  • 17.
    mid- to latetwentieth century – knowledge of biological structures and processes local anaesthetic 17 antiarrhythmic
  • 18.
    anticholinesterase •1970s and 1990s– molecular modeling and combinatorial chemistry 18
  • 19.
    Current trends inDrug discovery** ** It’s all a team work 19
  • 20.
    Drug Discovery Pipeline Lead discovery 20 Lead Optimization Candidate Selection Preclinical development Clinical developmentMarketing Hit Lead Preclinical Candidate Clinical Candidate NDA DRUG * takes 7-10 years to come to market with a new drug at costs ~ $ 150-800 million. ** extremely expensive test procedures required (preclinical and clinical tests)
  • 21.
    Post-marketing surveillance: collectionof adverse drug reaction data Regulatory Review: additional system that tracks long-term effects Development Research: Drug is given to an increasing number of individuals Phase III: 3000+ patients, half given drug under test, half given placebo Phase II: 200-400 patients receive the drug Phase I: 50-100 healthy volunteers Discovery research Identification of lead compounds: compds. shown to have biological activity Synthesis of analogues: many structurally related compounds are made and tested Biological evaluation of compounds: in vitro and in vivo testing. DRUG Drug development pyramid 21
  • 22.
    Clinical trial A clinicaltrial (also called clinical research) is a research study using human volunteers designed to determine the safety and effectiveness of a drug, biologic (such as a vaccine), device (such as a prothesis) or other treatment or behavioral intervention. 22
  • 23.
    23 • phase I: tests on healthy pharmacodynamics, toxicity). volunteers (pharmacokinetics, • phase II : tests on a limited number of persons with specific disease (efficacy). • phase III : global tests on broad clinical basis (definite safety, optimal dosage). • phase IV : registration, market support.
  • 24.
    24 Outcome of Pharmaceuticalresearch/ Drug Discovery • new products with enhanced activity • new products with diminished side effects • need of new products by increasing resistance • but on the other hand: • high development costs • unfavorable ratio between synthesized compounds and products on the market
  • 25.
    Leads and analogues:desirable properties • Bioavailability – Lipinski’s rule of five. • Solubility – lipophilicity and hydrophilicity. • Structure – stereo electronic properties. E.g. anticancer drug melphalan, centchroman. N Cl ClNH2 Melphalan O HO O centchroman O O N 25
  • 26.
  • 27.
    CH3 CH3 CH3 CH3 OO (R)-(+)- (S)-(-)- (S)-(+)- (R)-(-)- orange lemon caraway peppermint Biological effects of Enantiomers Limonene Carvone CHO OCH3 OH strong odor vanillin 27 CHO OH OCH3 no odor isovanillin
  • 28.
    • Stability -after administration and self-life. drug’s in situ stability A. modifying its structure. B. administering the drug as a more stable prodrug. C. using a suitable dosage form. treatment of glaucoma lasts for about three hours, needs 3–6 doses a day 28
  • 29.
    Drug stability bycomplex formation Prodrug stability • Self-life Self-life is the time taken for a drug’s pharmacological activity to decline to an unacceptable level. --- microbial degradation and adverse chemical reactions 29
  • 30.
    Sources of leadsand drugs • Originally drugs and leads were derived from natural sources Now- • Local folk remedies (Ethnopharmacology). • by serendipitously discovered (penicillin, Minoxidil, cisplatin etc.) • by structure-activity relationships (most) • by rational drug design (since the 80‘s) • High-throughput screening of compounds (since the 90‘s) • Databases and other literature sources of organic compounds. 30
  • 31.
    Ethnopharmaceutical sources: • Quininefrom cinchona bark - Antimalarial • Reserpine isolated from Rauwolfia serpentina – Antidepressant • Digitalis purpurea - digitoxigenin, gitoxigenin – Congestive heart failure. * Cardenolides: having an α,β unsaturated γ lactone ring. Or butyrolactone ring. Eg. digitoxin, digitoxigenin, digoxin, etc * Bufadienolides/Scilladienolides: containing a δ ring having a conjugated diene system. Or -pyrone ring eg. Bufotalin. 31
  • 32.
    • Plant sources– Taxol Taxus breifolia Vincirstine Vinca rosea Linn Morphine opium poppy Compounds with antifungal activity isolated from fungus resistant African plants • Animal sources – adrenaline and insulin 32
  • 33.
    • Marine sources– Avarol an immunodeficiency virus inhibitor. sponge Disidea avara Ara-A antiviral sponge T ethya crypta. cephalosporin C fungus Acremonium chrysogenium • Micro organism source – Benzylpenicillin (penicillin G) Penicillin notatum Streptomycin Streptomyces griseus 33
  • 34.
    Classification of drugs •Drugs are classified in different ways depending on where and how the drugs are being used. • On the basis of Pharmacological Activity • On the basis of chemical structure • On the basis of origin (Natural, synthetic, semi-synthetic, biosynthetic) 34
  • 35.
    35 This classification listsdrugs according to the nature of their pharmacodynamic behavior. Pharmacological Activity • Analgesics: Analgesics are the class of compounds that relieve pain. The all sort of pains such as headaches, backaches, joint pain etc., and pain that result from surgery, injury or illness. Among the most common Analgesics are Aspirin, Choline Salicylate, Magnesium Salicylate and Sodium Salicylate
  • 36.
    • Non-steroidal Anti-inflammatoryDrugs (NSAIDs) : relieve pain, swelling, stiffness, and inflammation. NSAIDs are prescribed for a variety of painful conditions, including Arthritis, Gout, sprains, strains, and other injuries. Non-steroidal Anti-inflammatory Drugs relieve pain, stiffness, swelling, and inflammation, but they do not cure the diseases or injuries responsible for these problems. Ibuprofen, Naproxen Sodium and Ketoprofen are Non-Steroidal Anti- Inflammatory Drugs (NSAIDs). NSAIDs relieve pain and also reduce inflammation. Another common analgesic, Acetaminophen provides pain relief but does not reduce inflammation. COOH NHCOCH3 COOH OCOCH3 OH Ibuprofen 36 ParacetamolAsprin
  • 37.
    Vasodilators : Vasodilatorsare substances that act directly on muscles in blood vessel walls to make blood vessels widen (dilate). Vasodilators are used to treat high blood pressure (hypertension). By widening the arteries, these drugs allow blood to flow through more easily, reducing blood pressure. Diuretics : Substances that increases the removal of fluids from the body. Diuretics are used for many reasons. They may be indicated for people who suffer from edema, an intense accumulation of fluids in the body's tissues, and those who suffer from high blood pressure or other heart related diseases. Hypnotic : drugs are a class of psychoactive drugs whose primary function is to induce sleep and to be used in the treatment surgical anesthesia. Benzodiazepines, Nonbenzodiazepines 37
  • 38.
    38 • Antiseptics: Antisepticsare substances that slow or stop the growth of germs and help prevent infections in minor cuts, scrapes, and burns. Antiseptics are applied to the skin to keep bacteria from getting into wounds and causing infection. Although Antiseptics do not usually kill bacteria, they do weaken them and slow their growth.
  • 39.
    Chemical structure • Classificationby means of chemical structure is useful to medicinal chemists who are concerned with synthesis and structure–activity relationships. 39
  • 40.
    • Sulphonamides: aresynthetic bacteriostatic antibiotics with a wide spectrum against most gram-positve and many gram- negative organisms. NH2 NH2 COOH PABA Involved in synthesis of DHFA, THFA and folate co-factor SO2NHR sulphonamide inhibit the synthesis of DHFA, THFA and folate co-factor N NO2 H S NH2N Sulphadiazine O2 H2N S NHCOCH3 Sulphacetamide O2 SH2N NH2 Dapsone 40
  • 41.
    • Quinolones: Theseclass of compounds constitutes a large numbers of synthetic antimicrobials agents that are highly effective in the treatment of many types of infectious disease, particularly those caused by bacteria. N R5 O COOHF R7 N O COOHF N ON H3C CH3 R8 R1 Fluoroquinolones R1 R5 R7 R8 Norfloxacin Ciprofloxacin Ofloxacin C2H5 NHNH H NHNH H C8 O CH3 NNH 41 1,8 Bridge Ofloxacin
  • 42.
    On the basisof origin Natural : Plants- Animals- Microorganisms- and Minerals- Synthetic : Semi-Synthetic : Biosynthetic : human insulin, interferon, vaccines 42
  • 43.
  • 44.
    O O O O H O H CH3 H CH3 H3C NaBH4H3C Methanol O O H O O CH3 H CH3 H OH O O H O O CH3 CH3 H H3C OMe H MeOH, HCl Artemether O O O O H H Artemisinin CH3 44 H CH3 H3C OMe Artether EtOH, HCl
  • 45.
    45 Physiological classification World HealthOrganization (WHO) 1. Agents acting on the central nervous system (CNS). psychotropic drugs neurological drugs 2. Pharmacodynamic agents. 3. Chemotherapeutic agents. 4. Miscellaneous agents.
  • 46.
    Methods and routesof administration • parenteral or enteral : Parenteral routes are those which avoid the gastrointestinal tract (GI tract) • intramuscular injection (IM). • intravenous injection (IV) • subcutaneous injection (SC) • transdermal delivery systems • Nasal sprays and inhalers are also parenteral routes. • The enteral route is where drugs are absorbed from the alimentary canal (given orally, PO), rectal and sublingual routes. 46
  • 47.
    The different methodsof administering drugs 47 Method of Administration Anatomical Entryway Description / Efficiency Examples Oral taken by mouth Slow very convenient. Rate of absorption into the bloodstream from the stomach is low. Absorption occurs mostly in the small intestine tablets, pills, liquids Inhalation vapour breathed in Fast Passes directly to the bloodstream via the lungs respiratory medications for asthma Rectal (suppositories) insertion into the rectum Moderately-Fast absorption from the large intestine to the bloodstream digestive illness treatments, hemorrhoids Intravenous injection into vein Fastest precise amounts can be administered and absorption into the blood is fastest of all methods local anesthetics
  • 48.
    48 Intramuscular injection intomuscle Slowest relatively safe; therefore, larger amounts of the drug may be administered vaccines Subcutaneous injection directly into fat under the skin Medium Speed work best when administered in a constant area, especially in the thigh, upper arm, or waist dental injections Other: skin patches; eye or ear drops placed on skin; liquid given directly Varies skin patch: absorption from the skin into the blood eye/ear drops: liquid delivered directly often targets a single central area, usually that of infection hormone treatment; infection treatment nicotine patches
  • 49.
  • 50.
  • 51.
    • The doseof a drug administered to a patient is the amount that is required to reach and maintain the concentration necessary to produce a favourable response at the site of biological action. Too high a dose usually causes unacceptable side effects, whilst too low a dose results in a failure of the therapy. • The limits between which the drug is an effective therapeutic agent is known as its therapeutic window. • The amount of a drug the plasma can contain, coupled with elimination processes that irreversibly remove the drug from its site of action, results in the drug concentration reaching a so-called plateau value. A simulation of a therapeutic window for a drug, given in fixed doses at fixed time intervals (") 51
  • 52.
    52 • The doseof a drug and how it is administered is called the drug regimen. Drug regimens may vary from a single dose taken to relieve a headache, regular daily doses taken to counteract the effects of epilepsy and diabetes, to continuous intravenous infusions for seriously ill patients. Regimens are designed to maintain the concentration of the drug within the therapeutic window at the site of action for the period of time that is required for therapeutic success.
  • 53.
    Introduction to DrugDesign and Action Chapter II 53
  • 54.
    54 Drug Design - Tominimize the trial and error approach. Requires a detailed study of Pharmacodynamics.
  • 55.
    55 Drug Action The actionof a drug is believed to be due to the interaction of that drug with enzymes, receptors and other molecules found in the body.
  • 56.
    56 Mode of Drugaction • Killing foreign organisms: the action of chemotherapeutics. • Stimulation and depression: the action of SERMS • Irritation: irritant action on gastrointestinal tract. • Replacement: Insulin is used in diabetes
  • 57.
    57 Sites of Drugaction – Enzyme : Drug-Receptor Interaction : Non-Specific Interaction : Antacids
  • 58.
    58 Drug-Receptor Interaction : Ionicinteraction Dipole-dipole interaction Hydrogen bonding Hydrophobic interaction Van der Waal forces Covalent interaction Charge transfer interaction
  • 59.
  • 60.
    Binding of ester-typelocal anesthetic agents to a receptor site 60
  • 61.
    Ionic Interactions - Strongelectrostatic Interactions (5-10 kcal/mol) - Responsible for relative orientation of the drug to its binding site H N S O O- N O O + H3N HN O 61
  • 62.
    Hydrogen Bonding Interactions(non-ionic/neutral) - Non-covalent bonds - Bond strength is distance dependent - Distance between the heteroatoms is about 2.2-3.5 Å N H N His, Try N H O H O O H H O 62
  • 63.
    Hydrophobic/lipophilic Interactions - Mostimportant interactions under physiological conditions - Come into play at closer distance than Ionic interactions - Binding of hydrophobic regions of a ligand in a hydrophobi pocket results in gain in entropy - Important role in many properties: Drug formulation, distribution etc. O N N 63
  • 64.
    (a) hydrophobic bondingand (b) London dispersive forces 64
  • 65.
    B B B B B B B B Drug residue DNA Chain DNAChain B B BH2 H2B H2B BH2 HB BH Drug Covalent bond formation Base Intrastrand cross-link Intrastrand cross linking through covalent bonds 65 E.g. action of Nitrogen mustard.
  • 66.
    H N N N H N E.g. N S CN Anticancercompound 41 Shaikh et al. Bioorg. Med. Chem. Lett. 2006, 16, 5917 66
  • 67.
    Drug-Receptor interactions Receptor surfacemodel with hydrophobic regions mapped on it. Hydrophobic regions are shown in brown and hydrophilic regions are shown in white. Compound 41 is placed within the generated receptor surface. Receptor surface model with hydrogen bonding propensity mapped on it. Hydrogen bond donor regions are shown in purple, while hydrogen bond acceptor regions are shown in cyan color. Compound 41 is placed within the generated receptor surface. 67
  • 68.
    N H N S NH N 41 Docked conformationof compound 41 (grey) in the binding site. All the hydrogen atoms of the protein are removed for clarity. Hydrogen bonds are shown with dotted red lines. N N 68
  • 69.
    69 • Receptor: Receptors arespecific areas of certain proteins that are found either embedded in cellular membranes or in the nuclei of living cells which serve to recognize the endogenous or exogenous (drug) molecule and initiate response to it.
  • 70.
    The fluid mosaicmodel of membranes 70
  • 71.
    signal transduction. Effects ofligands binding to receptors 71
  • 72.
  • 73.
    73 Drug action • Pharmacokineticphase: The study of the parameters that control the journey of the drug from its point of administration to its point of action. • Pharmacodynamic phase: the chemical nature of the relationship between the drug and its target, in other words, the effect of the drug on the body.
  • 74.
    74 The Pharmacokinetic phase(ADME) what the body does to the drug…
  • 75.
    Absorption...The passage ofthe drug from its site of administration into the general circulatory system after enteral administration. • Filtration: (Most pores have a diameter of 0.6–0.7 nm, which allows the passage of species with relative molecular masses up to about 100) • Passive diffusion : along the concentration gradient. 75
  • 76.
    • Facilitated diffusion: It involves specific carrier proteins known as permeases. It only occurs in the direction of the concentration gradient. • Active transport: It also involves carrier proteins but the movement is against the concentration gradient. 76
  • 77.
    77 • the pHof the medium from which absorption occurs. • the drug’s partition coefficient. • the drug’s dosage form. • the drug’s particle size. • for orally administered drugs, in either solid or emulsion form, their rate of dissolution. Absorption depends on…
  • 78.
    78 Distribution…It is thetransport of the drug from its initial point of administration or absorption to its site of action. • In form of solution of drug molecules or bound to the serum proteins, usually albumins. Drug = Drug-Serum Protein complex • In designing drug regimens. • Drugs with poor water solubility to reach their target site. • The drug–protein complex acts as a depot. • Protein binding can also increase the duration of action
  • 79.
    • Major factorsthat influence distribution are the solubility and stability of drugs in the biological environment of the blood. • … Concept of prodrug. • The distribution pattern of a drug through the tissues forming the blood vessels will depend largely on the nature of the tissue. 79
  • 80.
    • Influence ofdrug’s lipophilicity in its distribution. 99.6% 98.5% polar endogenous compounds such as amino acids, sugars, nucleosides and small ions (Na+, Li+, Ca2+ and K+) are also able to cross the BBB. 80
  • 81.
    Metabolism…Drug metabolism isthe biotransformation of the drug into other compounds (metabolites) that are usually more water soluble than their parent drug and are usually excreted in the urine. • These biotransformations occur mainly in the liver but they can also occur in blood and other organs such as the brain, lungs and kidneys. • … Concept of prodrug 81
  • 82.
  • 83.
    Excretion... Excretion isthe process by which unwanted substances are removed from the body. • The main excretion route for drugs and their metabolites is through the kidney in solution in the urine And via bowel in the faeces. • …case of thalidomide S-Thalidomide Teratogenic 83 R-Thalidomide Sedative
  • 84.
    • Prodrugs... Prodrugsare compounds that are pharmacologically inert but converted by enzyme or chemical action to the active form of the drug at or near their target site. E.g. levodopa, used to treat Parkinson’s syndrome, is the prodrug for the neurotransmitter dopamine. Dopamine is too polar to cross the blood–brain barrier but there is a transport system for amino acids such as levodopa. Once the prodrug enters the brain it is decarboxylated to the active drug dopamine 84
  • 85.
  • 86.
    86 The pharmacodynamic phase whatthe drug does to the body…
  • 87.
    87 • PD isdetermined by the stereoelectronic property of the drug. • The stereoelectronic structure should be complementary to that of the target site. • The binding may have stimulating or inhibiting activity. • The bonding is due to weak electrostatic bonds such as hydrogen bond and van der Waals’ forces. • Or Permanent binding due to covalent bonds.
  • 88.