Drug Discovery 4 Flashcards
why is it not good to have a lipid solubility of drugs over 5 ?
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
what is Lipinskis “rule of five”?
it is used to determine whether a drug is a good drug
- molecular mass of <10
what is combinatorial chemistry ?
enables chemists to combine several chemical building blocks in many different ways resulting in large numbers of different compounds
collection of compounds= combinatorial library
how is combinatorial chemistry carried out ?
it is an automate chemical synthesis method using robotics, computational automation and chemical building blocks
what happens after carrying out a high throughput sequencing process?
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
what is the aim of “LEAD FINDING”?
aim is to reduce the number of candidates
hit to lead
what analysis is undertaken to look at the confirmed hits?
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
what happens after producing the combinatorial library of confirmed hits ?
in vitro screens used to assess target specificity
pharmacokinetic analysis is carried out in vitro and in vivo
toxicity tests are carried out
what is the aim of “LEAD OPTIMISATION”?
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
what is a drugs pharmacophore?
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
what is the usual reason for un drug like molecules failing ?
normally due to poor pharmacokinetic properties which can lead to poor efficacy in vivo or toxicity
what factors are pharma trying to achieve ?
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
what factors are important for the delivery of a drug ?
good solubility
good permeability
high oral bioavailability
what factors are important for the elimination of a drug ?
absence of drug-drug interactions
low clearance/good half life
what does DMPK stand for ?
drug metabolism and pharmacokinetics
what are the 5 key areas which need to be optimised in DMPK?
bioavailability controlling CNS exposure metabolite identification clearance avoiding drug to drug interaction
what 3 metabolic barriers do orally administered drugs have to transverse before reaching general circulation ?
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
what is the phenomenom first pass effect ?
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
what does pre systemic clearance mean ?
loss of drug by first pass metabolism before it reaches the systemic blood circulation
what does fa stand for ?
fraction of drug that enter the intestinal lining
what does fg stand for ?
fraction of drug that survives the intestinal first pass metabolism
what does fh stand for ?
fraction of drug that survives first pass metabolism
how is the fraction of bioavailable drug determined?
F= fa x fh x fg
the amount of drug that enters the intestinal lining is dependent upon ?
instability in GIT fluids disintegration and dissolution rates solubility polarity and ionisation substrate for p-glycoprotein (p450s)
what is one of the most important factors that affects the bioavailability of a solid drug ?
dissolution
dissolution rates are often the rate determining step
what happens when a solid tablet disintegrates in the gut ?
it releases granules and these breakdown to release fine particles of solid drug
what are the 2 categories that contribute to the dissolution of drugs ?
those aaffecting the dissolution rate of the drug per se
those originating from the dosage form
what equation describes the dissolution of solids ?
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
what is the dissolution rate directly dependent upon ?
surface area and solubility
what factors are affecting the dissolution rate of the drug entity ?
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
what is a drug called that has no crystalline structure?
amorphous form
generally more soluble than its crystalline form
what factors of dissolution originate from the dosage form?
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
how is bioavailability predicted?
using lipinskis rule of 5
used to analysis the physical and chemical properties of drugs
what are the properties of a drug that suggest poor diffusion or absorption ?
- 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
what method can be used to estimate fa during lead optimisation?
caco-2 monolayers
what are caco-2 cells ?
human colon carcinoma cell line
many characteristics of the small intestinal enterocytes - they are polarised and have microvilli
what assay can be used to determine fg during lead optimisation ?
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
how can fh be determined?
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
