Lecture 13 - balancing potency with DME in drug development Flashcards
what does drug discovery and development need to account for?
This process needs to account for:
potent & selective activity against the target protein associated with the clinical disease
achieving said activity at the desired concentrations in a physiological system by ensuring:
good bioavailability - enough of drug into system
a robust metabolic profile - not cleared to rapidly or have to take too frequently leading to poor compliance
how do drugs bind to targets?
paclitaxel - spindle poison that binds to tubular
methotrexate - antimetabolite that binds to DHFR
what are features of different functional groups and how they are determined?
non polar, aliphatic side groups such as CHCH3CH3 and aromatic side groups such as C6H5. Have a short range. they are repulsive and attractive
Polar uncharged side groups such as CH2OOH, CHC(CH3, OH). Are mid range bonds they are electron deficient - electronegative atom with lone pair O, N, F.
Positively charged side groups such as H2N+ch2ch2. long range ionic.
what is lipinskis rule of five?
determines whether a drug has good oral absorption
No more than 5 hydrogen bond donors
No more than 10 hydrogen bond acceptors
Molecular weight less the 500
A LogP of less than 5
what does drug development need to consider?
modification of physicochemical properties to facilitate absorption via oral administration. drug development has to consider solubility, membrane permeability, lipophilicity, pKa, stability, CYP450 and plasma protein binding.
what are requirement for oral absorption?
- drug has to be water soluble to enable rapid dissolution in GIT
rapid dissolution and water solubility is favoured by ionisation, so drug tends to be formulated as salts ionised in solution - once dissolved rapidly in water, has to partition from water into lipoid membrane of GI tarts. to do this we need non-ionised lipophilic form of drug which is pH dependant.
unionised state = lipophilic. have to have pKa that allows them to move between ionised and unionised at physiological pHs
what is the selection of targets of drugs development?
new drug must have clinical offer
must be capable to b profitable.
the improvement on existing drugs must be substantial
drug with less side effects more demanding
afford?
how was gefitinib precursor meolcuel to gefitiniib final developed?
addition of fluorine and chlorine groups to gefitinib molecule forms a hydrophobic site which can be modified to block metabolism
and tertiary amino with a charge to improve solubility as it is a salt
why is driving potency and selectivity at the receptor level important?
all kinases bind to ATP. so if designing molecule to inhibit binding of ATP to your target kinase then molecule can also inhibit ATP binding to other kinases, and these kinases may be essential.
what is linpinskis rule of 5
Lipinskis rule of 5 is to determine whether a drug has good oral absorption
1. no more than 5 hydrogen bond donors
2. no more than 10 hydrogen bond acceptors
3. molecular weight less than 500
4. a lopgP less than 5
what are requirement of a drug for oral absorption ?
- the drug has to be water soluble to enable rapid dissolution in GIT.
rapid dissolution and water solubility is favoured by ionisation. so our drug molecules tend to be formulated as salts because salts ionise in solution.
- once dissolved rapidly in water, the drug has to partition form water into he lied membrane of the GIT. to do this, we need the non-ionised lipophilic form of the dug which is pK dependant
unionised state = lipophilic. have to have pKa that allows them to move between ionised state at physiological pHs.
what are the requirement for intravenous administration?
Drug has to be administered as a solution, which is soluble in solution - ionised form. so drug formulated as a salt, which allows ionisation of the molecule in this form.
describe the development of chlormethine.
chlormethine is the first alkylating mustard. highly reactive with nuecophiels and toxic f administered orally.
the nitrogen atoms has lone pairs which attack the electron deficient carbon and displaces chlorine. forms a 3 emmebrered ring which is extremely reactive and attached by nutreophiel. egegenratign a covert link. lien pairs on nitrogen then react with other chlorine
to make is less reactive, add benzene ring to the nitrogen. this still makes is less reactively deco lazing Leo pairs into the benne ring. generates the 3 membrane ring more slowly, so less reactive in GIS, however this lead to poor water solubility.
poor solubility = poor bioavailability
introduce polarity/ stable forming group to improve water solubility, for example, attach a carboxylic acid chain to the benzene ring.
explain the development of antioestrogenes
certain breast cancers proliferate when oestrogen receptors in the tumour cells are stimulated by estradiol. tamoxifen blocks estradiol action by competitive binding to reduce proliferation and induce tumour regression.
explain the properties of tamoxifen as an antioestrogene agent
Highly lipophilic regions binds to the oestrogen receptor - very poor solubility and low bioavailability. however, the solvent exposed region where the drug interaction with the protein is no as important. water soluble group that can be formulated as an HCL salt to promote solubility and oral administration. does not impair PD and promotes PK.
