SARs Flashcards

1
Q

How can the size and shape of compounds be changed?

A

Number of methylene units - increased lipophilicity

Degree of unsaturation - double bonds

Addition/removal of ring system

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2
Q

How do methylene groups increase activity?

A

Due to increases in lipid solubility which aids membrane penetration

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3
Q

How do methylene groups decrease activity?

A

Molecules that are too lipophilic are poorly water-soluble and so poor distribution and trapping of analogues in biological membrane is observed

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4
Q

What does increasing the degree of unsaturation in a molecule usually do?

A

Usually increases the affinity/activity of the analogue

Can lead to epoxides or other reactive metabolites forming however

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5
Q

Why would the activity of an analogue increase if a new ring system is added?

A

It means that there must be an additional hydrophobic pocket - Rolipram is a good example of this.

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6
Q

Why is cyclopropane often used instead of a C=C double bond?

A

Analogue is considerably more stable than double bond counterpart

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7
Q

Give an example of a ring system being used for its sterics

A

Penicillin G —> Methiciliin

Closer ring and addition of methoxy groups help resist ß-lactamase cleavage of drug - is still acid sensitive though

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8
Q

What is structure pruning? Give an example.

A

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

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9
Q

What’s an issue with methylated phenyl rings?

A

They’re very susceptible to metabolism to carboxylic acids by P450 oxidation

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10
Q

What’s the issue with compounds containing heteroatoms that have methyl groups attached?

A

They’re frequently metabolised - demethylated

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11
Q

What is the definition of the Partition co-efficient?

A

It describes the hydrophobic character of a drug - measured in an octane/water mixture

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12
Q

What gives the Partition co-efficient P?

A

P = [drug in octanol] / [drug in water]

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13
Q

What does greater partition coefficient mean?

A

A greater P means the analogue is more lipophilic

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14
Q

What does chlorine substitution do?

A

Increases lipophilicity - more than a methyl group

Can have steric effects

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15
Q

What is the ClogP of benzene?

A

ClogP = 2.14

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16
Q

What does hydroxyl substitution achieve?

A

Increased water solubility

Provides site for Phase 2 metabolism - reducing drug half-life & toxicity through accumulation

Provides new H-bonding site

17
Q

What’re the effects of amines in drug compounds?

A

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

18
Q

Why’re aromatic amines often avoided in medicinal chemistry?

A

As aromatic amines can be metabolised to toxic metabolites

Eg. Aniline is P450 N-oxidised to a nitroso-phenyl metabolite - reactive

19
Q

What’re bioisosteres? Why are they employed?

A

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

20
Q

How do classical isosteres differ to bioiosteres?

A

Classical isosteres were defined as atoms/molecules that have identical outer shells of electrons

21
Q

What is the rationale for Fluorine substitution?

A

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

22
Q

Give an example of an important fluorine substituted molecule?

A

5-fluorouracil - anticancer agent

It’s an example of a transition state inhibitor

23
Q

What is the mechanism of action of 5-fluorouracil?

A

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

24
Q

What is an example of an SSRI? What’s its significance?

A

Prozac - has CF3 group which increases lipophilicity of the drug, allowing for brain penetration

Also prevents metabolism in the aromatic ring

25
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
26
What is primaquine?
It is an anti-malarial that has a range of side effects - includes haemotoxicity
27
How is primaquine metabolised?
Primaquine is hydroxylated and then oxidised to become a NAPQI analogue - haemotoxicity
28
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
29
What is the use of estradiol?
It is used to treat low levels of oestrogen in women
30
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
31
How is metabolism of estradiol stopped?
2 fluorine’s are added - one replacing a methyl ether - to para positions of phenyl rings
32
What does the addition of 2 F groups to estradiol result in?
50 fold greater potency in vivo
33
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
34
Give the mechanism for R-OMe to -OH using BBr3
35
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+
36
What is the reagent used to get F+?
NFSI Where R = Ph
37
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
38
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