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Lecture 6

Lecture 6 ben .docx

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University of Ottawa
Robert Ben

Lecture 6 -in terms of drug development, on average, it takes typically, 500 thousands compound to make an active drug, -2 classic approaches, 1) Disjunction approach: dissection, logical of a lead drug -both use the best existing lead structures, each group will work on one compound, 2) conjunction : -duration of action increasing the half life, moderate the dosage, neo f the classic things u see is -if you have a delayed release, you can have it for the rest of the day, in vitamins, drugs, in salbutamol, how to modify the alkyl group -cost -Generate a substrate with a higher potency -Reduce toxicity -Increase specificity -Increase the duration of action (half life) -Reduce the cost of production a)Disjunction: -Simpler and simpler analogs, systematically reduce it, the bear minimum effect you need, the idea is amide, methyl group u need, qsns u ask >? -Physostigmine, basically from pure alkaloid, over time its been systematically modified and cut, neostigmine, u can remove most of the core and keep the quad amine, and have the same effect, 1952 another mod, basically myodecration, getting a phenol grou, and still have activity -Systematic synthesis and evaluation of simpler and simpler analogs -This approach hones in and identifies the key structural moiety responsible for the pharmacological activity -e.g Physostiygmine structure development, neostigmine, edrophonium, all modified better anti cholinesterases b) conjunction approach: synthetic and evaluation of more complex, and complex analogs, incorporating all or most features of the lead compound combine 2 drugs, or different elements of drugs, what you do is in the target u need an amide, endol ring, phenol, how to incorporate all these together, 3 wasy : 1)molecular addition : taking 2 different groups, 2 different drugs, beramone, mixture of sedative, and its combined with analgesic, H’s bonding, 2 different drugs brought to one, you get both properties, the association of the 2 different drugs happems through weak forces, like (electrostatic forces, and Hydrogen bonding ), barbital and aminophenazone 2) molecular replication : association of dentical moieties through covalent bonds(often the same moiety), isoniazide, 1 line treatment of tuberculosis multivalency,of one element of a drug, duplet or triplet, the drug may be way better, mostly done with analgesics, metazonide, isoniazide, the effeicacy, is intensified when isoniazid is triplet, another e.g neostigmine, multivalency again 3)molecular hyberdization : Association of different or mixed moieties through covalent bonds taking all different types of moedies and put them together, -specific processes : 1-ring closures or ring opening 2- double bods introducing 3-chiral centers : usings chiral centers is cleaver in pharma introducing 4- taking bulke groups away 5-isosteric substitution 6-change relative position of groups 1-introduce double bond : -change stereoelectronic properties, negative charge -physiochemical properties cis-cinnamic acid : plant growth hormone, reduce it, completely inactive ,just taking the double bond away -classic anticancer agent, in alpha-beta position, simple double bond is added by an enzyme in our body 2-chiral center : very important, it has been recognized a long time ago -Thalidomide: morning sickness for women The human impact of the thalidomide, as a sedative for pregnant women, morning sickness, it was not marketed in USA FDA pharmacologist, FDA has to give the approval for it, she got bothered by animal models, because there is problems with the drug, she stoped it, and stood against all the agencies, and that one of the abnormalities was tratogenic for the fetus cause birth defects, for a while it was not until the late 60’s when they stopped use it in Canada, ppl went looked at the possibility of marketing, decided to work with one of the enantiomers, the drug was marketed as a racemic drug given the R forms (non toxic), within short time will get the other one S (metabolite is teratogenic to the fetus) -Ibuprofin : huge industry, classic analgesic, stomach ulcers, very effective analgesic *isosteric substitution : replaceing a group with another group with the same of steric, S form is anti inflammatory, R form is inactive F : tri floro methyl ketones it mimics tetrahedral, we don’t tend to find Selenium in our drug, gives garlic breath Non classic isosteres : groups that have a similar steric and arrangement of electronic configuration Procaine and procainamide -changing the position of groups : hydroxyl benzoic acid (salicycilic acid) plant hormone, anti acne, Chelation function against metal poisoning -chlorophenols : -are the main component of numbs the throat and kills bacteria, the chlorine, drops the acidity of the OH proton, if u change the Cl position, into the meta position the proton is not as acidic as before if you do the resonance the hybrid is very high in energy not antiseptic Drug latentiation (prodrugs): -takes a drug in an exact from, and coverted and lately active substace, if ur lucky the group u put on it to make it late drug, theat group helps transport the drug into specific active site -rely on some chemical interconversion -reasons : 1-prolong the action, becus of the rate deterimining step, dose the drug 2-localizati, transport problems, more lipophilic, hydrophobic interaction, push that into the cell 3-avoid toxicity problems Dapsone antbacterial agent, combined with another drugs to fight leprosy, make a prodrug, more hydrophobic, and get into the cell =, once in the cell the peptidase cleave the group and activate the drug, avoiding toxicity and also helped transported where it needs to go, -Drug localization, classic example is chemotherapy, we relying on the fact that tumor selectively uptake chemotherapeutic substances, tumor cells metabolically active 100 times fold than normal cell, terrible side effects , becuz ts not selective -this is applicable to another types of drugs many diff examoles, ppl like to use carrier molecules, which we attach to a drug make it prod rug, oxine, potnt antoimicrobial agent, mechanism, tends to kill bacteria by sequencering iron, bact needs iron, make it very difficult for bact, the problem is other cells in oiur bodies is relying on blood, glycocylate the drug, glucose derivative, setting like this inactive, this carrier molecule rely on specific enzyme on our body, and cleave off the sugar and make it active -liposome sequester are also used -antibodies attached where it can direct , also used -it always a balance Lecture 6b -in terms of designing the drugs -SAR: is taking a target molecule and figure out the key structure on the molecule to have the desired effect, not only special arrangement, function of stability -Physiochemical properties, solubility (lipophilic interaction), distribution coefficient(for tissues) (solubility problems, so hydrophobic) relevant to toxicity, also, Thermodynamic properties. -some drugs needs liver function test every two weeks 1-Solubility: def : is the degree of interaction between a dru
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