Drug Discovery 4

Question 0

why is it not good to have a lipid solubility of drugs over 5 ?

Answer 0

because most of the drug will become stuck to membranes and unable to max concnetration at the site of action

however drugs with a low logP value are then not easilt absorbed because they cannot cross the bilayers

Question 1

what is Lipinskis “rule of five”?

Answer 1

it is used to determine whether a drug is a good drug

- molecular mass of <10

Question 2

what is combinatorial chemistry ?

Answer 2

enables chemists to combine several chemical building blocks in many different ways resulting in large numbers of different compounds
collection of compounds= combinatorial library

Question 3

how is combinatorial chemistry carried out ?

Answer 3

it is an automate chemical synthesis method using robotics, computational automation and chemical building blocks

Question 4

what happens after carrying out a high throughput sequencing process?

Answer 4

the hits produced are analysed for structural relationships- this will include artefacts and hopefully some good hits
then its important to carry out the primary assay again, with more concentrations of ligand or to do a secondary assay
the secondary assay is used to determine if a hit produced in the primary assay is genuine

Question 5

what is the aim of “LEAD FINDING”?

Answer 5

aim is to reduce the number of candidates

hit to lead

Question 6

what analysis is undertaken to look at the confirmed hits?

Answer 6

look to see if any of them fall within a family of related compounds
can any pharmacokinetic or toxicity issues be determined
the hits are resynthesised to check accuracy and to assess synthetic feasibility
once these hits have been confirmed to be ok then combinatorial chemistry is used

Question 7

what happens after producing the combinatorial library of confirmed hits ?

Answer 7

in vitro screens used to assess target specificity
pharmacokinetic analysis is carried out in vitro and in vivo
toxicity tests are carried out

Question 8

what is the aim of “LEAD OPTIMISATION”?

Answer 8

the aim is to optimise the efficacy and ADME/T of the lead compound

understand the structure-activity relationship of your lead compound(s)…. the pharmacophore

Question 9

what is a drugs pharmacophore?

Answer 9

is its structural features which are essential for efficacy
it is the analysis of many similar compounds which enables the structure activity relationships of that compound to be determined

Question 10

what is the usual reason for un drug like molecules failing ?

Answer 10

normally due to poor pharmacokinetic properties which can lead to poor efficacy in vivo or toxicity

Question 11

what factors are pharma trying to achieve ?

Answer 11

efficacy and safety
but also oral activity- easiest means of administration
convenient dosing regimen - drug that can be taken daily is better
no cross interactions with other drugs/foods

Question 12

what factors are important for the delivery of a drug ?

Answer 12

good solubility
good permeability
high oral bioavailability

Question 13

what factors are important for the elimination of a drug ?

Answer 13

absence of drug-drug interactions

low clearance/good half life

Question 14

what does DMPK stand for ?

Answer 14

drug metabolism and pharmacokinetics

Question 15

what are the 5 key areas which need to be optimised in DMPK?

Answer 15

bioavailability
controlling CNS exposure 
metabolite identification 
clearance
avoiding drug to drug interaction

Question 16

what 3 metabolic barriers do orally administered drugs have to transverse before reaching general circulation ?

Answer 16

intestinal lumen - digestive enzymes, insulin and bacteria can sometimes metabolise drugs
intestinal wall- perform a range of metabolic reactions on drugs- intestinal first pass metabolism
liver- major site of metabolism - hepatic first pass metabolism

Question 17

what is the phenomenom first pass effect ?

Answer 17

first passage of drug from gut lumen into the body - most if not all orally given drugs are subject to first pass metabolism to some degres

Question 18

what does pre systemic clearance mean ?

Answer 18

loss of drug by first pass metabolism before it reaches the systemic blood circulation

Question 19

what does fa stand for ?

Answer 19

fraction of drug that enter the intestinal lining

Question 20

what does fg stand for ?

Answer 20

fraction of drug that survives the intestinal first pass metabolism

Question 21

what does fh stand for ?

Answer 21

fraction of drug that survives first pass metabolism

Question 22

how is the fraction of bioavailable drug determined?

Answer 22

F= fa x fh x fg

Question 23

the amount of drug that enters the intestinal lining is dependent upon ?

Answer 23

instability in GIT fluids
disintegration and dissolution rates
solubility 
polarity and ionisation 
substrate for p-glycoprotein (p450s)

Question 24

what is one of the most important factors that affects the bioavailability of a solid drug ?

Answer 24

dissolution

dissolution rates are often the rate determining step

Question 25

what happens when a solid tablet disintegrates in the gut ?

Answer 25

it releases granules and these breakdown to release fine particles of solid drug

Question 26

what are the 2 categories that contribute to the dissolution of drugs ?

Answer 26

those aaffecting the dissolution rate of the drug per se

those originating from the dosage form

Question 27

what equation describes the dissolution of solids ?

Answer 27

noyes-whitney equation 
dc/dt=KACs
dc/dt= rate of dissolution 
K=constant
A= surface area of undissolved solute
Cs= solubility of the drug in the solvent

Question 28

what is the dissolution rate directly dependent upon ?

Answer 28

surface area and solubility

Question 29

what factors are affecting the dissolution rate of the drug entity ?

Answer 29

PARTICLE SIZE- smaller will increase rate and increased SA may increase bioavailability as long as absorption is dissolution rate limited INFLUENCE OF CRYSTAL FORM - many organic compounds exist in 2 or more crystals whihc is known as polymorphism and each crystal is a polymorph - the different ones have different properties such as differing solubilities

Question 30

what is a drug called that has no crystalline structure?

Answer 30

amorphous form

generally more soluble than its crystalline form

Question 31

what factors of dissolution originate from the dosage form?

Answer 31

INFLUENCE OF ADDITIVES- excipients are added to the formula but have no therapeutic action - although they are suppose to be inert, thy have been found to influence bioavailability
INFLUENCE OF TYPE OF DOSAGE FORM - oral dosage form e.g. aqueous, tablet, capsule. tablets are often coated to mask taste, smell or to prevent atmospheric degradation or to control the site of absorptopn

Question 32

how is bioavailability predicted?

Answer 32

using lipinskis rule of 5

used to analysis the physical and chemical properties of drugs

Question 33

what are the properties of a drug that suggest poor diffusion or absorption ?

Answer 33

• more than 5 hydrogen bond donors (sum of Os and Hs)
• more than 10 hydrogen bond acceptors (sum of Ns and Os)
• molecular weight is >500
• logP is greater than 5 - substrates that are able to use membrane transporters are exceptions

Question 34

what method can be used to estimate fa during lead optimisation?

Answer 34

caco-2 monolayers

Question 35

what are caco-2 cells ?

Answer 35

human colon carcinoma cell line

many characteristics of the small intestinal enterocytes - they are polarised and have microvilli

Question 36

what assay can be used to determine fg during lead optimisation ?

Answer 36

intestinal microsomal CYP assays
microsomes are artificial membrane aggregates made from ruptured homogenised intestinal cell - contain the CYP proteins needed to 1st pass metabolism
investigate metabolism of test compounds

Question 37

how can fh be determined?

Answer 37

hepatocyte culture and hepatic microsomal CYP assays
test to see if drug is a substrate for phase 1 and phase 2 hepatic metabolism
microsomes are prepared from hepatocyte for phase 1
low through put and complex assay can be used to assess phase 2 using cultured hepatocytes