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									1. An Introduction to Drugs,
Their Action and Discovery


  The basic concepts in Medicinal
             Chemistry
             1.1 Introduction
• Primary objective- design and discovery of new
  compounds that are suitable for use as drugs
• A team of workers- chemistry, biology,
  biochemistry, pharmacology, mathematics,
  medicine and computing, amongst others
• Requires of drug discovery or design- synthesis
  of the drug, a method of administration, the
  development of tests and procedures to establish
  how it operates in the body, and a safety
  assessment
• Drug discovery may also require fundamental
  research into the biological and chemical
  nature of the diseased state.
• Medicinal chemists need to have an outline
  knowledge of the above mentioned aspects.
1.2 What are drugs and why do we need new
                  ones?
• Definition of drug -chemical substances that
  are used to prevent or cure diseases in humans,
  animals and plants
• Activity - pharmaceutical/pharmacological
  effect on the subject, e.g. analgesic or β-
  blocker
• Potency - the quantitative nature of the effect
• The word “Drug” usually defined as agent used
  for the psychotic effect by the media or general
  public.
• Even the drugs abused have their activity.
• Drugs act by interfering with biological processes,
  so no drug is completely safe.
• That is, suitable quantity to cure or excess to be
  poisonous! E.g. aspirin, paracetamol can be toxic
  if excesses.
• Side effect – unwanted effect usually; however,
  they are not always non-beneficial
• For example, the drowsiness side effect of
  anti-histamine may help sleep.
• Drug resistance or tolerance (tachyphylaxis)
  occurs when a drug is no longer effective in
  controlling a medical condition.
• Reasons – induced oxidases in the liver that
  are able to metabolize the drug; a special
  enzyme induced to metabolize the drug; down
  regulated drug receptors
            Therapeutic index

• Chemotherapeutic index = Minimum curative
  dose /Maximum tolerated dose
• By Ehrlich in search of a safer antiprotozoal
  agent in 19th century -- more effective drugs
  showed a greater selectivity for the target
  microorganism than its host
• Therapeutic index = LD50/ED50
  1.3 Drug discovery and design: a
         historical outline
• Origin of drugs – natural products from plants,
  animals, and/or minerals since ancient time
• Drugs ↔ Poison = pharmakon in Greece, and the
  criteria can be ‘quantity’ usually
• Information about usages and toxicity of drugs
  were limited by communication until the
  invention of printing press in 15th century→
  Herbals and Pharmacopeia↑ → drug misuse or
  abuse ↑ →→ the ineffective and/or more toxic
  preparations removed by the practitioners
      Evolution and revolution
• Early 19th – plant extracts and pure isolates
  from medicinal plants appearedSome of these
  drugs were very toxic
• Late 19th, to find less toxic medicines than
  those based on natural sources → synthetic
  substances as drugs
• Early 20th synthetics dominated the main
  origin of therapeutic drug origins
• Leads – the known pharmacologically active
  chemicals used in drug design and
  development
• Analogues – the-lead related compounds
            Therapeutic index
• Paul Ehrlich and Sacachiro Hata who produced
  arsphenamine in 1910 – in the search of more
  effective anti-microbiotic agents: Atoxyl,
  Arsphenamine (Salvarsan)
                          Minimum curative dose
    Therapeutic index 
                          Maximum tolerated dose


                          ED50
    Therapeutic index 
                          LD50
• The term structure–activity relationship (SAR)
  is now used to describe Ehrlich’s approach to
  drug discovery, which consisted of
  synthesizing and testing a series of structurally
  related compounds (see Chapter 3).


                               H2N                      NH2
                       ONa                                         HClx2
        H2N            As O   HO           As As              OH
                       OH
              Atoxyl               Arsphenamine (Salvarsan)
  QSAR – quantitative structure–activity
             relationship
• 1960s that Hansch and Fujita devised a method
  that successfully incorporated quantitative
  measurements into structure–activity
  relationship determinations
• The most successful uses of QSAR has been in
  the development in the 1970s of the antiulcer
  agents cimetidine and ranitidine.
• Both SAR and QSAR are important parts of
  the foundations of medicinal chemistry.
      Concept of Drug Receptor
• In 1905 John Langley proposed that so-called
  receptive substances in the body could accept
  either a stimulating compound, which would
  cause a biological response, or a non-stimulating
  compound, which would prevent a biological
  response.
• Receptor sites (Chap. 8) usually take the form of
  pockets, grooves or other cavities in the surface of
  certain proteins and glycoproteins in the living
  organism.
• Ligand – The binding of a chemical agent,
  referred to as a ligand, to a receptor sets in
  motion a series of biochemical events that
  result in a biological or physiological effect.
• Stereoelectronic structure: Both as regards
  molecular shape and electron distribution, is
  complementary with the stereoelectronic
  structure of the receptor responsible for the
  desired biological action.
• The drug conformation adopted when binds to
  the receptor is known as active conformation.
• The section of the structure of a ligand that binds
  to a receptor is known as its pharmacophore.
• E.g., the “quaternary nitrogens” that are believed
  to form the pharmacophore of the neuromuscular
  blocking agent tubocrarine are separated in the
  molecule by a distance of 115.3 nm.
                          H3CO
                                                 + CH3
                                                         2Cl-
                                               N
                              HO           (R)
                                               H CH3
                                       O     CH2

                      H2C
                      H            O
                  H3C +
                      N (S)                OH
                    H
                                       OCH3
                      (+)-Tubocurarine chloride
• Esters and N-substituted amides, for example,
  have structures with similar shapes and
  electron distributions but N-substituted amides
  hydrolyze more slowly than esters.
• However, changing a group or introducing a
  group may change the nature of the activity of
  the compound.          O
                                  R'
                                     O
                       R'
                            O   R             N   R
                                              H
                            Ester            Amide
                                O                         O
                   N                         N
                            O                         N
                                                      H
                                       NH2                      NH2
                         Procaine             Procainamide
                       (anaesthetic)         (antiarrhythmic)
                        Membranes
• Drugs normally have to cross non-polar lipid
  membrane barriers (see sections 7.2 and 7.3) in
  order to reach their site of action. As the polar
  nature of the drug increases it usually becomes
  more difficult for the compound to cross these
  barriers.
           HN       O               N       O
                                N
                O                       O             N+
                            N
                Physostigmine           Neostigmine
          Modern Techniques
• Computerized molecular modeling (1970s) –
  allows the researcher to predict the three-
  dimensional shapes of molecules and target,
  calculate the binding energy, and reduced the
  need to synthesize every analogue of a lead
  compound
• Combinatorial chemistry (1990s) – originated
  in the field of peptide chemistry but has now
  been expanded to cover other areas.
• simultaneous production of large numbers of
  compounds, known as libraries, for biological
  testing.
• Used for structure–activity studies and to
  discover new lead compounds.
• The procedures may be automated.
    1.4 Leads and analogues: some
         desirable properties
• Bioavailability – Lipinski’s rules to predict a
   molecule to be likely orally bioavailable
1. a molecular mass less than 500;
2. a calculated value of log P* less than 5;
3. less than ten hydrogen bond acceptor groups (e.g.
   -O- and -N-, etc.);
4. less than five hydrogen bond donor groups (e.g.
   NH and OH, etc.).
⃰ P = partition coefficient of octanol/water
                 Solubility
• Any compounds that are potential drug
  candidates have to be soluble to some extent in
  both lipid and water.
• Ideal leads and/or analogues have a balance
  between their water solubility and their
  lipophilicity.
                 Structure
• The nature of the structures of leads and
  analogues will determine their ability to bind
  to receptors and other target sites.
• Binding forces between a drug and a receptor –
  electrostatic bonds, such as hydrogen bonds
  and van der Waals’ forces, ion pair, and
  covalent bond                    Cl

                                      N
                 HOOC
                          NH2                Cl
                            Melphalan
                        DNA Alkylating agent
• A major consideration in the selection of leads
  and analogues is their stereochemistry.
• It is necessary to pharmacologically evaluate
  individual enantiomers as well as any
  racemates.

  Cl        N                                    OH
                                                                     (Z)
                                   (E)


            N                                         HO
        H            N   HO
                                  7                         100
                              (potency)                  (potency)
       chloroquine                                                    OH
        R=S form                         diethylstilbestrol
                  Stablility
• Stability after administration and shelf-life
• Three strategies are commonly used for
   improving a drug’s in situ stability:
1. modifying its structure; prepare a more stable
   analogue with the same pharmacological
   activity
2. administering the drug as a more stable
   prodrug
3. using a suitable dosage form
            Create a more stable analogue

                                                  OH
                      Hydrolysis                   OH
N                 O                N                      N            O
    N                  pH=7.4           N                     N    N
                                                   O
                  O                                                    O
    Pilocarpine                        Pilocarpic acid   Carbamate analogue
      (active)                            (inactive)
                Forming a complex
• Cyclodextrins are bottomless flower-pot-
  shaped cylindrical oligosaccharides consisting
  of about 6–8 glucose units. The exterior of the
  ‘flower-pot’ is hydrophilic in character whilst
  the interior has a hydrophobic nature.
• water solubility, bioavailability and
  pharmacological action ↑
• ↓ side effects
              Prodrug formation

     H                          H
    N O                       HN O
     P                          P
    O N        Cl             HO N        Cl


       Cl                         Cl
Cyclophosphamide         Phosphoramidate mustard
                 Shelf-life
• Shelf-life is the time taken for a drug’s
  pharmacological activity to decline to an
  unacceptable level.
• 10 % decomposition is often taken as an
  acceptable limit provided that the
  decomposition products are not toxic.
• deterioration – microbial degradation and
  adverse chemical interactions and reactions
• Adverse chemical interactions between the
  components of a dosage form can also be
  avoided by the use of suitable excipients.
• Decomposition by chemical reaction – heat,
  light, atmospheric oxidation, hydrolysis by
  atmospheric moisture and racemization

								
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