Lecture #2 Flashcards
despite aspirin being used foe centuries. when did we discover its mechanism of action?
around the 19th century
describe the alkaloid class:
large and complex groups of cyclins that contain at least one nitrogen atom
how is aspirin able to work?
it is able to covalently release the acidic group and block COX1 / COX2 and this enables the activation of specific enzymes responsible for the anti-inflammatory activity
what is the difference in structure between coding and morphine?
codine has a methyl group → the presence of the methyl reduces the analgesic activity of the molecule by 90%
what is papaverine and what is it used for?
can trigger muscle and blood vessel relaxation - used in cardiovascular diseases to counteract potential heart attacks
what two natural products are used to treat malaria?
quinine and artemisinin
what is the mechanism of action assumed to be for artemisinin?
there is an oxygen-oxygen bond that seems responsible for certain radical scavenger activity and is useful for the treatment of malaria
what are the two main groups of drugs today?
natural products and those derived from natural products
why is it rare nowadays to have a natural product be considered as a chemical starting point for optimization?
- molecules are too complex - complexity may be associated with better specificity, however the downside is that molecules derived from natural products may be too difficult in terms of synthetic transformation
- complexity and decoration of scaffolds - typically natural products are highly hydrophilic which is not idea for oral absorption
what is the quality of the molecule very much dependent on?
the ability of the chemist to give diversity to the synthesized compound
describe the current phenotypical screening:
the characterization of the New Chemical Entity can be performed in animal models or cell based says to see whether they exert a specific biological effect by altering a behavioral phenotype
what does the mechanism of action of NCE require?
a downstream target deconvolution process
what primary screening assay has been used where the HBV is transiently expressed?
EPA-D 38 - a cell line of hepatoblasomta in which it is possible to express HBV
what do target-based assays investigate?
the detailed molecular ligand-target interaction hypothesis
what was the first benzodiazepine tranquilizer drug?
Librium
describe the mechanism of action for benzodiazapines:
these molecules are positive GABA-A modulators, so they are able to increase the frequency of the opening of the ion channel associated to GABA-A (neurotransmitter that is the major inhibitor in neurons), paired with Cl- → they increase the ability of GABA-A to antagonized the excitability of the neurons
what is the first member of the tricyclic family that is mainly used to treat depression but also antipsychotic agent for bipolar disorder and schizophrenia?
Imipramine
what was the model A of drug discovery described as?
the “needle in a haystack” paradigm → based on serendipity and no information about the biological target
what two main drugs were discovered during the model A time period?
benzodiazepines and Imipramine
what years did model A of drug discovery span over?
1950-1970
what were the main issues with model A?
- lack of a sufficient number of molecules with a suitable degree of structural diversity (molecules obtained were too similar to each other)
- compounds were randomly rested in vivo regardless of their chemical structure
- in-vivo animal models were used as the main filter for progression
what were the three major downsides to animals being used as the main filter for progression in model A of drug discovery?
- lack of pharmacokinetic information
- unknown biological mechanisms
- presence of side effects because no one was investing in selectivity
what is cisplatin?
an inorganic compound that is one of the most effective anti-cancer agents particularly for ovarian and testicular tumors
how is cisplatin used?
nosocomial: IV administration as a mono therapy or in combination
how is the active form of cisplatin obtained?
after the systemic administration, water displaces the chlorine residue getting a chlorine-water complex that is able to link to specific nitrogen residues present at the n7 position of guanines, blocking the intra-strand or inter-strand DNA
what does the blocking of intra-strand or inter-strand DNA by cisplatin cause?
the DNA inter strands cross linking chelation at specific guanines less to the creation of localized unwound regions of the DNA helix causing the inhibition of transcription
what is the main issue with the use of cisplatin?
the development of cross-resistance which is due to the immediate activation of the DNA repair mechanism
besides cross-resistance, what other negative affect does cisplatin have?
associated with severe side effects - but it may be combined with Ondonsetron (HT3 antagonist) or Aprepitant (NK1 receptor antagonist) to get rid of the toxicity
what are the two safer analogies to cisplatin?
Carboplatin and Oxaliplatin
what time period did Model B span over?
form 1970-1990
What was different between model A and model B?
They started to link a defined chemical structure for the recognition of specific families(G coupled receptors)
What was the model B period characterized by?
The discovery of biological targets: a number of different receptors, their classifications, and also the link of the receptor to the pathogenesis of the specific disease
What 2 characterization steps occurred in model b?
In-vivo and in-vitro characterization
How were the in-vitro assays used?
Central to obtain info about how to modify known molecules to optimize the recognition of the drug
What is “developability”?
All aspects necessary to progress the molecule
What is a blockbuster?
An extremely popular drug that generates annual sales of at least $1 billion
What was the 1st blockbuster drug?
Histamine 2 antagonist (h2 ants)
What was the aim of the project when h2 ants was discovered?
They wanted to counted the baseline level of acidity in the stomach responsible for the gastro-oralpharyngeal reflux
Also to identify the antagonist responsible for the control of the acidity in the stomach over 24 hours
What was the first H2 ANTS molecule identified?
Cimetidine
What were the limitations of cimetidine?
- it was given at least twice a day (sometimes 3)
- Associate with undesired CNS side effects
What was the improved version of cimetidine?
Ranitidine ( Zantac)
How was ranitidine better?
Given once a day and was unable to cross the BBB so there were no CNS side effects
What is possible to get from an agonist?
An antagonist → key stopping point is the natural agonist (histidine) - by looking at the structure of histidine you can recognize immediately the same type of heterocycle and the presence of the lefthand side side-chain bearing a polar residue
Most compounds that progress to development fail due to:
- Poor pharmacokinetics in humans (39%)
- Lack of clinical efficacy (29%)
- Toxicity and adverse events (21%)
- Commercial limitations (6%)
What must a new dung nowadays have in order to be approved?
Must be significantly better than what is already registered
