SARs

Question 1

How can the size and shape of compounds be changed?

Answer 1

Number of methylene units - increased lipophilicity

Degree of unsaturation - double bonds

Addition/removal of ring system

Question 2

How do methylene groups increase activity?

Answer 2

Due to increases in lipid solubility which aids membrane penetration

Question 3

How do methylene groups decrease activity?

Answer 3

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

Question 4

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

Answer 4

Usually increases the affinity/activity of the analogue

Can lead to epoxides or other reactive metabolites forming however

Question 5

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

Answer 5

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

Question 6

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

Answer 6

Analogue is considerably more stable than double bond counterpart

Question 7

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

Answer 7

Penicillin G —> Methiciliin

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

Question 8

What is structure pruning? Give an example.

Answer 8

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

Question 9

What’s an issue with methylated phenyl rings?

Answer 9

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

Question 10

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

Answer 10

They’re frequently metabolised - demethylated

Question 11

What is the definition of the Partition co-efficient?

Answer 11

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

Question 12

What gives the Partition co-efficient P?

Answer 12

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

Question 13

What does greater partition coefficient mean?

Answer 13

A greater P means the analogue is more lipophilic

Question 14

What does chlorine substitution do?

Answer 14

Increases lipophilicity - more than a methyl group

Can have steric effects

Question 15

What is the ClogP of benzene?

Answer 15

ClogP = 2.14

Question 16

What does hydroxyl substitution achieve?

Answer 16

Increased water solubility

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

Provides new H-bonding site

Question 17

What’re the effects of amines in drug compounds?

Answer 17

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

Question 18

Why’re aromatic amines often avoided in medicinal chemistry?

Answer 18

As aromatic amines can be metabolised to toxic metabolites

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

Question 19

What’re bioisosteres? Why are they employed?

Answer 19

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

Question 20

How do classical isosteres differ to bioiosteres?

Answer 20

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

Question 21

What is the rationale for Fluorine substitution?

Answer 21

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

Question 22

Give an example of an important fluorine substituted molecule?

Answer 22

5-fluorouracil - anticancer agent

It’s an example of a transition state inhibitor

Question 23

What is the mechanism of action of 5-fluorouracil?

Answer 23

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

Question 24

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

Answer 24

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

Also prevents metabolism in the aromatic ring

Question 25

Why is fluorine added to paracetamol?

Answer 25

It increases its oxidative stability, decreasing its toxicity and hence reduces the depletion of hepatic glutathione conjugate - making it a much safer drug

Question 26

What is primaquine?

Answer 26

It is an anti-malarial that has a range of side effects - includes haemotoxicity

Question 27

How is primaquine metabolised?

Answer 27

Primaquine is hydroxylated and then oxidised to become a NAPQI analogue - haemotoxicity

Question 28

How does F substitution prevent primaquine metabolism?

Answer 28

5-fluoro substitution blocks hydroxylation of primaquine, ceasing its metabolism to NAPQI analogue

5-fluoroprimaquine maintains pharma properties and is less toxic

Question 29

What is the use of estradiol?

Answer 29

It is used to treat low levels of oestrogen in women

Question 30

What’s the issue with estradiol?

Answer 30

They are known to undergo P450 mediated 2-hydroxylation, forming a catechol which oxidises to a toxic ortho quinone

Question 31

How is metabolism of estradiol stopped?

Answer 31

2 fluorine’s are added - one replacing a methyl ether - to para positions of phenyl rings

Question 32

What does the addition of 2 F groups to estradiol result in?

Answer 32

50 fold greater potency in vivo

Question 33

What’re the 3 main approaches to synthesising fluorinated drugs?

Answer 33

Using commercially available building blocks

Using N-Fluoro reagents - F+ sources

Using nucleophilic sources of fluorine

Question 34

Give the mechanism for R-OMe to -OH using BBr3

Answer 34

Question 35

Give the mechanism of the Halex reaction

Answer 35

It is simply F- acting as a nucleophile at a site with a good leaving group

Requires large counter-ions - Cs+ or Bu4N+

Question 36

What is the reagent used to get F+?

Answer 36

NFSI

Where R = Ph

Question 37

What’s the definition of a pharmacophore?

Answer 37

An abstract description of a molecular feature that is required for a ligand to be recognised by a biological target

Question 38

Whats the definition of a core fragment?

Answer 38

A core fragment is a specific fragment that has a highly conserved binding pose and an effective affinity contribution to the binding