BBS3016 Pharmacological
Interventions
Case 1
1. What are the different phases of drug development?
1. Drug discovery, during which candidate molecules are chosen on the basis of their
pharmacological properties.
- Target identification
This comes from biological intelligence Conventional biological wisdom,
drawing on a rich fund of knowledge of disease mechanisms and chemical
signalling pathways, coupled with genomic data, is the basis on which novel
targets are most often chosen. Disciplines such as genomics, bioinformatics,
proteomics and systems analysis are playing an increasing role by revealing
new proteins involved in chemical signalling, new genes involved in disease
and new models of disease progression.
- Lead finding
- Lead optimisation
2. Preclinical development, during which a wide range of non-human studies (e.g. toxicity
testing, pharmacokinetic/pharmacodynamic analysis and formulation) are performed.
3. Clinical development, during which the selected compound is tested for efficacy, side effects
and potential dangers in volunteers and patients.
1
,2
,2. Explain the extraction of acetyl salicylic acid from the willow bark tree.
a. large scale synthesis and newly developed organic synthetical techniques
The story of the discovery of aspirin stretches back more than 3500 years to when bark from the
willow tree was used as a pain reliever and antipyretic.
The active ingredient in willow bark was not discovered until 1828 when Johann Buchner (1783–
1852) first refined willow bark into yellow crystals and named it Salicin (after Salix, the genus of the
willow tree) (Schindler, 1978). In 1829, the process was further refined by Pierre-Joseph Leroux
(1795–1870) in France (Leroux, 1830) and taken a step further in 1838 when Raffaele Piria (1814–
1865) produced a stronger compound from the crystals isolated from willow bark, which he named
salicylic acid.
In 1852, the French chemist, Charles Gerhardt (1816–1856), was the first to modify salicylic acid with
the introduction of an acetyl group in place of a hydroxyl group, but the compound was not stable
(Gerhardt, 1853). Gerhardt has one of the first true claims to be the person to discover aspirin but
the lack of stability of his newly derived compound stopped him from developing it further.
Acetylation of salicylic acid later proved to be the key step in reducing its irritant properties.
Large-scale synthesis enables drug discovery, clinical development, and commercialization for new
small molecule medicines
3
, 3. What’s the difference in effects on the stomach between acetyl salicylic acid and salicylic acid?
And how is acetyl salicylic acid modified?
a. Structure-activity relationships
b. how is Aspirin metabolised in the body?
The fenotyl group (of the saclicylic acid( is more irritating for the stomach than the acetyl group
(acety salicylic acid).
Structure-Activity Relationship (SAR) is an approach designed to find relationships between chemical
structure (or structural-related properties) and biological activity (or target property) of studied
compounds.
SAR tools like CDD Vault can detect correlations and build models used to evaluate new chemical
structures to predict their biological activity. They can then be applied to building desirable new
compounds and characterizing them. Existing compounds can be further evaluated using SAR for
likely side-effect activities.
https://info.collaborativedrug.com/tofu-content-what-is-sar
Aspirin metabolism
Acetylsalicylic acid is a prodrug with a short half-life (approximately 20 minutes) because of rapid
hydrolysis to salicylic acid by serine esterases in the intestinal wall, erythrocytes, and liver.
SA is mainly metabolized by the liver into its
glycine conjugate, salicyluric acid, and its
glucuronic acid conjugates, salicyl phenolic
glucuronide and salicyl acyl glucuronide.
These products are excreted by means of
organic anion transporters in the proximal
tubule of the kidney, where they can compete
for uric acid excretion. Only about 10% of
unchanged SA is freely excreted by the kidney.
4.
What are non steroidal anti inflammatory Figure 1: Salicylate Toxicity, Biff F. Palmer, M.D., and Deborah J. Clegg, Ph.D.
drugs (NSAIDs) and what are their anti inflammatory actions?
a. cyclooxygenase enzymes (COX1 & COX2, inducible isoform & pathway)
4
Interventions
Case 1
1. What are the different phases of drug development?
1. Drug discovery, during which candidate molecules are chosen on the basis of their
pharmacological properties.
- Target identification
This comes from biological intelligence Conventional biological wisdom,
drawing on a rich fund of knowledge of disease mechanisms and chemical
signalling pathways, coupled with genomic data, is the basis on which novel
targets are most often chosen. Disciplines such as genomics, bioinformatics,
proteomics and systems analysis are playing an increasing role by revealing
new proteins involved in chemical signalling, new genes involved in disease
and new models of disease progression.
- Lead finding
- Lead optimisation
2. Preclinical development, during which a wide range of non-human studies (e.g. toxicity
testing, pharmacokinetic/pharmacodynamic analysis and formulation) are performed.
3. Clinical development, during which the selected compound is tested for efficacy, side effects
and potential dangers in volunteers and patients.
1
,2
,2. Explain the extraction of acetyl salicylic acid from the willow bark tree.
a. large scale synthesis and newly developed organic synthetical techniques
The story of the discovery of aspirin stretches back more than 3500 years to when bark from the
willow tree was used as a pain reliever and antipyretic.
The active ingredient in willow bark was not discovered until 1828 when Johann Buchner (1783–
1852) first refined willow bark into yellow crystals and named it Salicin (after Salix, the genus of the
willow tree) (Schindler, 1978). In 1829, the process was further refined by Pierre-Joseph Leroux
(1795–1870) in France (Leroux, 1830) and taken a step further in 1838 when Raffaele Piria (1814–
1865) produced a stronger compound from the crystals isolated from willow bark, which he named
salicylic acid.
In 1852, the French chemist, Charles Gerhardt (1816–1856), was the first to modify salicylic acid with
the introduction of an acetyl group in place of a hydroxyl group, but the compound was not stable
(Gerhardt, 1853). Gerhardt has one of the first true claims to be the person to discover aspirin but
the lack of stability of his newly derived compound stopped him from developing it further.
Acetylation of salicylic acid later proved to be the key step in reducing its irritant properties.
Large-scale synthesis enables drug discovery, clinical development, and commercialization for new
small molecule medicines
3
, 3. What’s the difference in effects on the stomach between acetyl salicylic acid and salicylic acid?
And how is acetyl salicylic acid modified?
a. Structure-activity relationships
b. how is Aspirin metabolised in the body?
The fenotyl group (of the saclicylic acid( is more irritating for the stomach than the acetyl group
(acety salicylic acid).
Structure-Activity Relationship (SAR) is an approach designed to find relationships between chemical
structure (or structural-related properties) and biological activity (or target property) of studied
compounds.
SAR tools like CDD Vault can detect correlations and build models used to evaluate new chemical
structures to predict their biological activity. They can then be applied to building desirable new
compounds and characterizing them. Existing compounds can be further evaluated using SAR for
likely side-effect activities.
https://info.collaborativedrug.com/tofu-content-what-is-sar
Aspirin metabolism
Acetylsalicylic acid is a prodrug with a short half-life (approximately 20 minutes) because of rapid
hydrolysis to salicylic acid by serine esterases in the intestinal wall, erythrocytes, and liver.
SA is mainly metabolized by the liver into its
glycine conjugate, salicyluric acid, and its
glucuronic acid conjugates, salicyl phenolic
glucuronide and salicyl acyl glucuronide.
These products are excreted by means of
organic anion transporters in the proximal
tubule of the kidney, where they can compete
for uric acid excretion. Only about 10% of
unchanged SA is freely excreted by the kidney.
4.
What are non steroidal anti inflammatory Figure 1: Salicylate Toxicity, Biff F. Palmer, M.D., and Deborah J. Clegg, Ph.D.
drugs (NSAIDs) and what are their anti inflammatory actions?
a. cyclooxygenase enzymes (COX1 & COX2, inducible isoform & pathway)
4
