SARs Flashcards
How can the size and shape of compounds be changed?
Number of methylene units - increased lipophilicity
Degree of unsaturation - double bonds
Addition/removal of ring system
How do methylene groups increase activity?
Due to increases in lipid solubility which aids membrane penetration
How do methylene groups decrease activity?
Molecules that are too lipophilic are poorly water-soluble and so poor distribution and trapping of analogues in biological membrane is observed
What does increasing the degree of unsaturation in a molecule usually do?
Usually increases the affinity/activity of the analogue
Can lead to epoxides or other reactive metabolites forming however
Why would the activity of an analogue increase if a new ring system is added?
It means that there must be an additional hydrophobic pocket - Rolipram is a good example of this.
Why is cyclopropane often used instead of a C=C double bond?
Analogue is considerably more stable than double bond counterpart
Give an example of a ring system being used for its sterics
Penicillin G —> Methiciliin
Closer ring and addition of methoxy groups help resist ß-lactamase cleavage of drug - is still acid sensitive though
What is structure pruning? Give an example.
Structure pruning is when parts of a molecule are removed, not the pharmacophore, to give different pharmacological profiles
Eg. Morphine derivatives such as methadone, still analgesic but has no addictive properties
What’s an issue with methylated phenyl rings?
They’re very susceptible to metabolism to carboxylic acids by P450 oxidation
What’s the issue with compounds containing heteroatoms that have methyl groups attached?
They’re frequently metabolised - demethylated
What is the definition of the Partition co-efficient?
It describes the hydrophobic character of a drug - measured in an octane/water mixture
What gives the Partition co-efficient P?
P = [drug in octanol] / [drug in water]
What does greater partition coefficient mean?
A greater P means the analogue is more lipophilic
What does chlorine substitution do?
Increases lipophilicity - more than a methyl group
Can have steric effects
What is the ClogP of benzene?
ClogP = 2.14
What does hydroxyl substitution achieve?
Increased water solubility
Provides site for Phase 2 metabolism - reducing drug half-life & toxicity through accumulation
Provides new H-bonding site
What’re the effects of amines in drug compounds?
They enhance water solubility - as they’re formulated as salts
Number of amine should be controlled - if molecule is too highly charged compound will not pass across biological membranes
Why’re aromatic amines often avoided in medicinal chemistry?
As aromatic amines can be metabolised to toxic metabolites
Eg. Aniline is P450 N-oxidised to a nitroso-phenyl metabolite - reactive
What’re bioisosteres? Why are they employed?
They are groups that exhibit some similarities in their physical and chemical properties
Employed as the isosteric replacement of a substituent in a drug compound is MORE LIKELY to produce an analogue with USEFUL properties
How do classical isosteres differ to bioiosteres?
Classical isosteres were defined as atoms/molecules that have identical outer shells of electrons
What is the rationale for Fluorine substitution?
C-F bond is inert to metabolic cleavage - strong bond
All has no steric impact on receptor sites wrt hydrogen
F can also act as H-bond donor acceptor
Increases lipophilicity of molecule
Can alter the oxidation potential of an aromatic system - prevents aminophenols to quinoneimines
Give an example of an important fluorine substituted molecule?
5-fluorouracil - anticancer agent
It’s an example of a transition state inhibitor
What is the mechanism of action of 5-fluorouracil?
Enzyme binds and uracil becomes methylated at 5 position, with fluorine.
F is then not kicked off and so 5FU is left covalently bound to the enzyme active site
What is an example of an SSRI? What’s its significance?
Prozac - has CF3 group which increases lipophilicity of the drug, allowing for brain penetration
Also prevents metabolism in the aromatic ring
Why is fluorine added to paracetamol?
It increases its oxidative stability, decreasing its toxicity and hence reduces the depletion of hepatic glutathione conjugate - making it a much safer drug
What is primaquine?
It is an anti-malarial that has a range of side effects - includes haemotoxicity
How is primaquine metabolised?
Primaquine is hydroxylated and then oxidised to become a NAPQI analogue - haemotoxicity
How does F substitution prevent primaquine metabolism?
5-fluoro substitution blocks hydroxylation of primaquine, ceasing its metabolism to NAPQI analogue
5-fluoroprimaquine maintains pharma properties and is less toxic
What is the use of estradiol?
It is used to treat low levels of oestrogen in women
What’s the issue with estradiol?
They are known to undergo P450 mediated 2-hydroxylation, forming a catechol which oxidises to a toxic ortho quinone
How is metabolism of estradiol stopped?
2 fluorine’s are added - one replacing a methyl ether - to para positions of phenyl rings
What does the addition of 2 F groups to estradiol result in?
50 fold greater potency in vivo
What’re the 3 main approaches to synthesising fluorinated drugs?
Using commercially available building blocks
Using N-Fluoro reagents - F+ sources
Using nucleophilic sources of fluorine
Give the mechanism for R-OMe to -OH using BBr3
Give the mechanism of the Halex reaction
It is simply F- acting as a nucleophile at a site with a good leaving group
Requires large counter-ions - Cs+ or Bu4N+
What is the reagent used to get F+?
NFSI
Where R = Ph
What’s the definition of a pharmacophore?
An abstract description of a molecular feature that is required for a ligand to be recognised by a biological target
Whats the definition of a core fragment?
A core fragment is a specific fragment that has a highly conserved binding pose and an effective affinity contribution to the binding
