Medicinal Chem Flashcards
What is the definition of medicinal chemistry?
Multidisciplinary science concerned with the design + synthesis of new chemical entities in order to produce new medicines for the prevent and cure of disease
Where is cholesterol made in the body
Liver at night
Why is cholesterol important and why can too much be bad?
Needed for membrane fluidity and permeability and is an important precursor for the manufacture of steroids and vitamin D. Too much can block arteries and may be linked To cardiovascular disease
What are LDLs
Low density lipoproteins - carry cholesterol around the body
Once level is too high ldl receptor is blocked so no cholesterol in the form of LDL can be taken up
What are the key stages in drug development
KS1 - disease studied and drug target identified
KS2- lead discovery
KS3 - lead optimisation
KS4 - preclinical studies
KS5- clinical trials and marketing
What is a lead compound?
A synthetically accessible chemical entity that produces the desired pharmacological activity
Must have suitable chemical and physiochemical properties
What the types of sources adopted to find the lead compound
Screening natural products or synthetic libraries
Why are few lead compounds not ideal?
Low selectively and activity and significant side effects
How can drug target interactions be improved
Once important binging sites and pharmacophores have been identified then synthetic analogies can be made
How can development attrition be reduced?
By optimising drug like properties of lead compound at early stages of development
What are drug like Properites
Once a that show acceptable ADME properties and taxicory properties in addition to desirable pharmacological properties
What is the dosage form?
They way in which medicine is administered
Give the three physical natures of the dosage forms
Liquids - emulsion, solutions and suspensions
semisolid formulations - gels and creams
Solid - capsules and tablets
What does the dosage form contain
The active ingredient and excipients
What are excipients
They are other ingredients that have a number or functions
Filler, binders, lubricants and preservatives and antioxidants
True or false - changing the nature of the excipients can significantly affect the release of the active ingredient from the dosage form?
True
What is the enteral route
Drugs absorbed through alimentary canal, rectal and sublingual routes (tissues in the tongue)
Unabsorbed material excreted through gastrointestinal tract
Make sure it doesn’t react inadvertently with food
Fescues the parental route?
Avoids the GT and administered by injections, intravenously or nasal sprays and inhalers
Excrete via kidney (urine) or lungs
Faster therapeutic effect
What are barriers to drug delivery?
Stomach - enzymes acids
GI- permeability and plasma proteins
Kidneys
Liver - metabolisms and bilateral excretion
True or false - the structural properties do not govern the physichemical and biochemical Properites of the drugs
False
What’s is lipophilicity?
The ability to dissolve in days, oils, lipids and non polar solvents
What happens if a compound is too lipophilic
May not dissolve in aq media and will bind too strongly to plasma proteins
May distribute in lipid bilayer and not cells
What happens is a compound is too polar
May not be absorbed by gut wall
What is the partition coefficient
A measure of the way a compound distributes itself among two immiscible solvents
What is the most common organic phase when measuring partition coefficients
Octanol
Because it has a polar and non polar region so mimics lipid bilayer
P is easy to measure and correlates well with biological Properties
Predicted accurately using computational methods
What does it mean if P is greater or less than 1
P>1 (log P >0) more lipophillic
P<1 (log P<0) more hydrophilic
What is the distribution coefficient
The effective lipophilicity of a compound at a given pH
Why is log D a better way of measure he lipophilicity of a compound
It takes into account that things ionise in aq solution as well as a function of the lipophilicity of the un ionised compound and the degree of ionisation
What is pharmacokinetics (PK)
The study of how a drug reaches its target and what happens during its journey
What does ADME
Absorption
Distribution
Metabolism
Excretion
What is pharmacodynamics?
Studies drug effect on the body (efficacy and toxicity)
What is adsorption?
Absorption through the gastrointestinal tract into circulatory system
Occurs in small intestines due to large surface area
Once in cell it is protonated so it can’t leave
What are P- glycoproteins and how can they reduce the bioavailability of a drug
They a efflux transporters and pimp put cytotoxic material out of cell. They are ATP driven and have a broad specificity so can remove drug from entering the cell.
How can the bioavailability of a drug be increased involving Pgp
Co administration with another compound that inhibits p- go
how does the drug bind with plasma proteins?
reversibly binding via H, dipole dipole and electrostatic int.
Dynamic equlibrium formed between bound and free drug in blood.
too much binding reduces its bioavailability
True or false: Acids and bases bind to the same site on Plasma proteins
false - they bind to different sites
How does Log D relate to plasma protein binding?
for basic and neutral drugs log d is proportional
it is higher for acids
the higher log d is the higher the binding
How are compounds distributed into cells?
pH gradient, Tissue pH is slightly lower than plasma pH. Basic compounds are distributed more into tissues than acidic compounds
what is metabolism?
the chemical reactions responsible for the conversion of the drug into other compounds either before or after it has reached site of action
Can metabolism occur via more than 1 route?
yeah more than 1 enzyme controlled routes.
What are the two different reactions that occur in metabolism?
Phase 1 and Phase 2
How can the speed at which a drug is metabolised have an effect on the bod?
Poor or slow metabolism - toxic
fast and extensive metabolism - poor activity
what are phase 1 reactions and where do they occur?
Oxidation, reduction and hydrolysis. In the liver mainly but also the gut wall and blood plasma
describe phase 1 oxidation?
Carried out by P450 enzymes, these contain a Heam protein.
Fe(III) in resting state. Reduced to Fe(II) by 1 electron ET. Oxygen reacts and a reactive oxygen species made by another ET. This can then react to form the appropriate product
describe phase 1 reduction?
Nitro groups to Amines or hydroxylamines N(OH)Rn
carbonyls to alcohols, ketones and aldehydes
describe phase 1 hydrolysis?
Amides/ esters to amines, alcohols and acids
what are phase II reactions and where do they occur?
Conjugation reactions
The addition of a group or molecule to the drug or metabolite.
In the liver
How do phase II reactions increase excretion rate?
the conjugated product is more polar
how are drugs and metabolites excreted from the body?
By the kidney and both via the same mechanism
what increases the likelihood of something being excreted?
the more polar or water soluble it is
describe the processes that occur in renal excretion?
- anything not bound to plasma protein is filtered in the glomerulus
- Can be excreted into urine along proximal tubing
- Unionised compounds can undergo passive re absorption from urine into blood along the length nephron
- Bound drug and metabolites will not be filtered.
what is the biliary excretion?
Transporters in liver tissue mediate the uptake of drugs and drug metabolite into tissue and efflux into bile. Bile builds up in gall bladder and released into intestine upon food uptake.