Medicinal Chemistry
Chapter 1: Introduction and Pharmaceutical Phase
1.0. Introduction
1.0.1. Some definitions
Medicinal Chemistry: the discovery, development, identification and interpretation of the
mode of action (MOA) of biologically active compounds at the molecular level. Biologically
active compounds are not only drugs, also EDCs for example. Metabolites are the breakdowns
of the products. Goal of medicinal chemistry: find, develop and improve drug substances that
cure or alleviate diseases and understand the causative and accompanying chemical
processes.
DA: new drug application => explains the rational behind the mode of action of the drug
Chemical biology: investigation of biological processes by chemical methods. Here no new
drugs are developed, but instead chemical libraries are screened.
Pharmacology: the study of biologically active molecules on organisms, such as cells, tissues,
animals … for animals, animal housing is used => all animals are brought in the same ‘state’
(weight, diet …) so that only 1 variable is allowed.
Molecular pharmacology: the mode of action of a biologically active compound on a
molecular level. This domain is less sensitive to biological variability in animals.
Clinical pharmacology: studies the effect of drugs on healthy volunteers and patients.
Physiology: studies how cells form organs and the functions of these organism in the body.
Comparing sick and healthy organs => information about the disease + link with cellular level
=> bias for rational drug design.
Medicine: studies the effect of diseases on the body, the healing or prevention of these my
means of vaccines, surgery, medication …
Pharmacy: the study of the formulation (tablets, syrups, aerosols…) of active molecules.
Biochemistry: studies the chemical processes in the cells of living organisms. Changes in these
processes can be a significant indication to design a new therapy.
Molecular biology: studies the physical and chemical structure of biomacromolecules such as
proteins and nucleic acids, DNA and RNA. Therapeutic macromolecules consist of antibodies,
proteins, growth hormone (GH), insulin …
1
,1.1. Biotech in medicinal chemistry
Three classes of drugs:
- Small molecules ( <1000 Da)
- Peptides
- Biologicals (multiple kDa) => drawback: 20-30x more expensive than small molecules
(R&D + production). Three types can be distinguished
• Human: biologicals originated from humans
• Humanized: non-human biologicals that are modified in such a way to be
resemble the human alternatives
• Chimeric: both humanized and longer non-human peptide stretches
Drugs are as expected most in 1st world develop countries due to the high cost associated to
them. FDA: the food and drug administration that controls the drug market in America. In
Europe we have the EMA: European medicines agencies.
The design of biological drugs is done by nature, the shape of the compound is based on ints
inherent properties. Their toxicity is overall lower than small molecules since they resemble
more naturally to nature. However, their cost is high + difficult reproducibility, formulation
(control pH, buffers, salts…) and production.
1.2. Historical overview
Before the 1800s, pharmacy remained an empiric science that was guided by traditional
chemistry => herbs, plant extracts … ≠ drug, which is a single biologically active compound.
At the turn of the 19th century characterization by extraction and purification were developed
=> more scientific approach. To date, plants and micro-organisms remain important sources
for new drugs (toxins, venom, bacteria and fungi…).
In 1805, morphine was discovered and works by binding the µ-opioid receptor and has pain-
killing effects. In 1819, quinine was isolated and has since then been used for treatment of
fever and malaria. In 1829 salicin was isolated:
When salicin is metabolized is loses its sugar moiety and upon oxidation of the 1° ROH,
salicylic acid is formed. Converting this acid to its sodium salt and acetylation the alcohol
functionality resulted in the development of aspirin => treatment of fever.
2
,A few years later, ether was used as an anesthetic and chloroform was used during surgeries.
Funnily enough the same researchers that developed aspirin, also discovered heroin
(acetylated version of morphine). In the beginning aspirin and heroin were co-advertised
together, but quickly enough heroin was removed from the market due to its high addiction
(related to the seek of dopamine release).
In 1929 penicillin was discovered, in 39 it was prepared for the first time and in 45 its structure
was confirmed. In 1958 haloperidol was discovered by Paul Janssen and used for antipsychotic
treatment.
In 67 L-dopa, precursor and agonist of dopamine was used to treat Parkinson’s disease. In
Parkinson many neuromodulators are killed, of which dopamine also is part. L-dopa can cross
the BBB, while dopamine itself can’t.
1.3. Drugs and drug substances
Drugs are composed of drug substances (active pharmaceutical ingredients = APIs) and
excipients (bulkup formulation). The combination of both => formulation.
The ideal new drug substance is:
- New chemical => can be patented
- Maximal 4-step synthesis, without a heavy metal catalyst, no environmental waste,
no chromatographic purification and still a purity > 99%.
- Stable up to 70°C even in humid air and in light
- Crystalline
- Sufficient solubility in water for the production of blood-isotonic solutions (= same salt
concentrations as blood)
- Oral bioavailability higher than 90% without interindividual variation
- High activity + PK profile enables once a-day-dosage at 5-10 mg
3
, 1.4. Classification of drugs
1.4.1. Classification by pharmacological effect
Examples of classes are: analgesics, antipsychotics, antibiotics …
The advantage of this classification is a full overview of compounds with the same effects is
obtained. On the other hand, the drawbacks are the structural features of the compounds
that differ strongly, besides their different MOA.
Example) Antibacterial agents
Antibacterial agents have 5 MOA:
1) Inhibition of cell metabolism
Succinyl sulfur thiazole is a sulfa drugs (= sulfur amide drugs), more precisely a prodrug: upon
metabolization of the prodrug, the biologically active compound is released. In this case, the
amide bond of the prodrug is hydrolyzed to the drug. The succinyl group was used to keep
the compound for extended periods in the intestines, but how? In the intestines, the pH is
slightly basic => deprotonation of the RCOOH to the RCOO- => ionic compound is less
lipophilic.
A drug must have a good balance between hydrophilicity (good water solubility) and a good
lipophilicity (hydrophobic) since membranes are lipid bilayers. In the graph above, the activity
of the drug in function of the lipophilicity (log P) is illustrated. Log P? P stands for the partition
coefficient:
compound concentration in the apolar phase
compound concentration in the polar phase
A too high lipophilicity results in a water insoluble drug, hence aggression in biological
systems (see example with the benzoyl). This was an example of a reversible inhibition.
4
Chapter 1: Introduction and Pharmaceutical Phase
1.0. Introduction
1.0.1. Some definitions
Medicinal Chemistry: the discovery, development, identification and interpretation of the
mode of action (MOA) of biologically active compounds at the molecular level. Biologically
active compounds are not only drugs, also EDCs for example. Metabolites are the breakdowns
of the products. Goal of medicinal chemistry: find, develop and improve drug substances that
cure or alleviate diseases and understand the causative and accompanying chemical
processes.
DA: new drug application => explains the rational behind the mode of action of the drug
Chemical biology: investigation of biological processes by chemical methods. Here no new
drugs are developed, but instead chemical libraries are screened.
Pharmacology: the study of biologically active molecules on organisms, such as cells, tissues,
animals … for animals, animal housing is used => all animals are brought in the same ‘state’
(weight, diet …) so that only 1 variable is allowed.
Molecular pharmacology: the mode of action of a biologically active compound on a
molecular level. This domain is less sensitive to biological variability in animals.
Clinical pharmacology: studies the effect of drugs on healthy volunteers and patients.
Physiology: studies how cells form organs and the functions of these organism in the body.
Comparing sick and healthy organs => information about the disease + link with cellular level
=> bias for rational drug design.
Medicine: studies the effect of diseases on the body, the healing or prevention of these my
means of vaccines, surgery, medication …
Pharmacy: the study of the formulation (tablets, syrups, aerosols…) of active molecules.
Biochemistry: studies the chemical processes in the cells of living organisms. Changes in these
processes can be a significant indication to design a new therapy.
Molecular biology: studies the physical and chemical structure of biomacromolecules such as
proteins and nucleic acids, DNA and RNA. Therapeutic macromolecules consist of antibodies,
proteins, growth hormone (GH), insulin …
1
,1.1. Biotech in medicinal chemistry
Three classes of drugs:
- Small molecules ( <1000 Da)
- Peptides
- Biologicals (multiple kDa) => drawback: 20-30x more expensive than small molecules
(R&D + production). Three types can be distinguished
• Human: biologicals originated from humans
• Humanized: non-human biologicals that are modified in such a way to be
resemble the human alternatives
• Chimeric: both humanized and longer non-human peptide stretches
Drugs are as expected most in 1st world develop countries due to the high cost associated to
them. FDA: the food and drug administration that controls the drug market in America. In
Europe we have the EMA: European medicines agencies.
The design of biological drugs is done by nature, the shape of the compound is based on ints
inherent properties. Their toxicity is overall lower than small molecules since they resemble
more naturally to nature. However, their cost is high + difficult reproducibility, formulation
(control pH, buffers, salts…) and production.
1.2. Historical overview
Before the 1800s, pharmacy remained an empiric science that was guided by traditional
chemistry => herbs, plant extracts … ≠ drug, which is a single biologically active compound.
At the turn of the 19th century characterization by extraction and purification were developed
=> more scientific approach. To date, plants and micro-organisms remain important sources
for new drugs (toxins, venom, bacteria and fungi…).
In 1805, morphine was discovered and works by binding the µ-opioid receptor and has pain-
killing effects. In 1819, quinine was isolated and has since then been used for treatment of
fever and malaria. In 1829 salicin was isolated:
When salicin is metabolized is loses its sugar moiety and upon oxidation of the 1° ROH,
salicylic acid is formed. Converting this acid to its sodium salt and acetylation the alcohol
functionality resulted in the development of aspirin => treatment of fever.
2
,A few years later, ether was used as an anesthetic and chloroform was used during surgeries.
Funnily enough the same researchers that developed aspirin, also discovered heroin
(acetylated version of morphine). In the beginning aspirin and heroin were co-advertised
together, but quickly enough heroin was removed from the market due to its high addiction
(related to the seek of dopamine release).
In 1929 penicillin was discovered, in 39 it was prepared for the first time and in 45 its structure
was confirmed. In 1958 haloperidol was discovered by Paul Janssen and used for antipsychotic
treatment.
In 67 L-dopa, precursor and agonist of dopamine was used to treat Parkinson’s disease. In
Parkinson many neuromodulators are killed, of which dopamine also is part. L-dopa can cross
the BBB, while dopamine itself can’t.
1.3. Drugs and drug substances
Drugs are composed of drug substances (active pharmaceutical ingredients = APIs) and
excipients (bulkup formulation). The combination of both => formulation.
The ideal new drug substance is:
- New chemical => can be patented
- Maximal 4-step synthesis, without a heavy metal catalyst, no environmental waste,
no chromatographic purification and still a purity > 99%.
- Stable up to 70°C even in humid air and in light
- Crystalline
- Sufficient solubility in water for the production of blood-isotonic solutions (= same salt
concentrations as blood)
- Oral bioavailability higher than 90% without interindividual variation
- High activity + PK profile enables once a-day-dosage at 5-10 mg
3
, 1.4. Classification of drugs
1.4.1. Classification by pharmacological effect
Examples of classes are: analgesics, antipsychotics, antibiotics …
The advantage of this classification is a full overview of compounds with the same effects is
obtained. On the other hand, the drawbacks are the structural features of the compounds
that differ strongly, besides their different MOA.
Example) Antibacterial agents
Antibacterial agents have 5 MOA:
1) Inhibition of cell metabolism
Succinyl sulfur thiazole is a sulfa drugs (= sulfur amide drugs), more precisely a prodrug: upon
metabolization of the prodrug, the biologically active compound is released. In this case, the
amide bond of the prodrug is hydrolyzed to the drug. The succinyl group was used to keep
the compound for extended periods in the intestines, but how? In the intestines, the pH is
slightly basic => deprotonation of the RCOOH to the RCOO- => ionic compound is less
lipophilic.
A drug must have a good balance between hydrophilicity (good water solubility) and a good
lipophilicity (hydrophobic) since membranes are lipid bilayers. In the graph above, the activity
of the drug in function of the lipophilicity (log P) is illustrated. Log P? P stands for the partition
coefficient:
compound concentration in the apolar phase
compound concentration in the polar phase
A too high lipophilicity results in a water insoluble drug, hence aggression in biological
systems (see example with the benzoyl). This was an example of a reversible inhibition.
4
