PSMA (PMOC) PT. 1

Medicinal chemistry

• is the science, which deals with the discovery and design of new and better therapeutic chemicals and development of these chemicals into new medicines and drugs

Medicinal chemists

• can make new compounds

• determine their effect on biological processes

• alter the structure of the compound for optimum effect and minimum side effects

• study uptake, distribution, metabolism and excretion of drugs

Random screening

• this is an approach in drug discovery wherein there is already an existing drug that can be used to identify a new lead compound

Stereochemistry

• space arrangement of the atoms or three-dimensional structure of the molecule

• positioning the different functional groups in their sites of action

• plays a major role in the pharmacological properites

• any change in stereospecificity of the drug will affect its pharmacological activity

• the isomeric pairs have different physical properties and thus differ in pharmacological activity

Isomers

• same molecular formula but are arranged differently in space

Constitutional isomers

• different sequence of bonds

Skeletal isomers

• have different carbon skeleton

Functional group isomers

• have different functional groups

Positional isomers

• same functional groups but at different positions

Stereoisomers

• same sequence of bonds but atoms oriented differently

Configurational isomers

• can be interconvented only by breaking and making bonds

Conformational isomers

• interconvertable by rotation around a single bond

Diastereomers

• non-superimposable

• non-mirror images

• (chiral or achiral)

• epimers

• cis-trans or E/Z isomers

Enantiomers

• non-superimposable

• mirror images (chiral)

Optical isomers

• are compounds that contain at least one chiral carbon atom

• are compounds that differ only in their ability to rotate the polarized light

Enantiomers

• can have large differences in potency, receptor fit, biologic activity, transport and metabolism

• these differences result when the drug molecule has a asymmetric interaction with a receptor, a transport protein, or a metabolizing enzyme

Ascorbic acid

only the (-) isomer of ___ has antiscorbutic activity

alpha and beta glucose

• only the D isomers of __ show high affinity for the red blood cell sugar transfer stem

alpha methyldopa

only the (-) isomer of ___ has hypotensive activity

chloramphenicol

• only the D(threo) isomer of ___ has high anti-bacterial activity

Geometric isomerism (cis-trans isomerisms)

• it occurs as a result of restricted rotation about a chemical bond, owing to double bonds or rigid ring system in the molecule

• not mirror images

• have different physicochemical properties and pharmacological activity

Conformational isomerism

• also known as rotamers

• these are non-superimposable orientation of a molecule which result from the rotation of atoms about single bonds

Optical isomerism

Classification of:

• D and L forms

• Mirror images

Geometric isomerism

Classification of:

• cis and trans forms

Conformational isomerism

Classification of:

• Eclipsed and staggered

Isosterism

• any two ions or molecules having an identical number and arrangement of electrons

Bioisosterism

• is the procedure of the synthesis of structural analogues of a lead compound by substitution of an atom or a group of atoms in the parent compound for another with similar electronic and steric characteristics

• as the phenomenon by which compounds usually fit the broadest definition of isosteres and possess the same type of biological activity

Bioisosterism

• important in medicinal chemistry because they maintain similar biological properties

• resolved biological problems effectively

Procainamide

• an amide, has a longer duration of action than procaine, an ester, because of the isosteric replacement of the ester oxygen with a nitrogen atom

Carbachol

• the acyl methyl group has been replaced by an NH₂

• resistance to hydrolysis is due to the electronic effect of the carbamate group

• chemical structure

• variation in particle size

• particle surface area

• nature of crystal form

• type of coating

• type of tablet matrix

Factors of oral administration

1. to reach the target site

2. to alter the solubility of drug

3. act as metabolic precursor

4. used to enhance the absorption/to improve the membrane permeability of its active metabolite

4 Prodrug approach for oral administration

Olsalazine

• used in ulcerative colitis

• a dimer of the pharmacologically active mesalamine (5-aminosalicylic acid)

• chloramphenicol + palmitic acid

__ + __ = chloramphenicol palmitate

• Chloramphenicol palmitate

a prodrug that reduces drug solubility

• menadione → vitamin K

an example of a prodrug that acts as metabolic precursor

• Enalapril

• Levodopa

• Pivampicillin

Examples of prodrugs that is used to enhance absorption/to improve the membrane permeability of its active metabolite

Enalapril

• ethyl ester of enalaprilic acid

• an active inhibitor of angiotensin-converting enzyme

• much more readily absorbed orally than the pharmacologically active carboxylic acid

Parenteral administration

• bypass the intestinal barrier

• common in patients who cannot tolerate or are incapable of accepting drugs orally

1. can be used to alter the solubility characteristics which can increase the flexibility in formulating dosage forms

2. prodrug can alter biodistribution and biological half-life

2 Prodrug approach for parenteral administration

methylprednisolone

• slightly water-insoluble

methylprednisolone acetate

• water-insoluble, top. Oint & aq. susp (IM)

methylprednisolone sodium succinate

• water-soluble, oral, IV, IM

methylprednisolone

methylprednisolone acetate

methylprednisolone sodium succinate

esterases

• both the succiate and acetate esters hydrolyzed to the active methylprednisolone by?

• methylprednisolone

• methylprednisolone acetate

• methylprednisolone sodium succinate

example of prodrug that can be used to alter the solubility characteristics which can increase the flexibility in formulating dosage forms

• retinoic acid structure

• etretinate

• acitretin

example of prodrugs that can alter biodistribution and biological half-life

retinoic acid structure

• used systemically to treat psoriasis, a nonmalignant hyperplasia

etretinate

• has a 120-day “terminal” half-life after 6 months of therapy

acitretin

• active metabolite

• has a 33- to 96-hour “terminal” half-life

etretinate

acitretin

protein binding

• drug + albumin → drug-albumin complex

• can affect solubility, biodistribution, half-life in the body, and interaction of the drug with other drugs

• limits access to certain body compartments

• can prolong the drug’s duration of action

• limits the amount of drug available for bio transformation and for interaction with specific receptor sites

suramin

• large polar trypanocide remains in the body in the protein-bound form as long as 3 months (t1/2 = 50 days)

• the maintenance dose: based on weekly administration

tissue depots

• the more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots

thiopental

• ultra-short acting, lipophilic barbiturate

• its concentration rapidly decreases below its effective concentration following administration

first pass effect

• initial trip of the drug through the liver

• lidocaine

• nitroglycerin

• morphine

• meperidine

drugs that are extensively metabolized by the first pass effect

regioselectivity

• denotes the selective metabolism of two or more similar functional groups, or two or more similar atoms that are positioned in different regions of a molecule

active sulfide metabolite

active metabolite of sulindac

6-mercaptopurine

active metabolite of azathioprine

azathioprine

• designed to prolong the drug activity of its active metabolite

paracetamol

active metabolite of phenacetin

desipramine

active metabolite of imipramine

nortriptyline

active metabolite of amitriptyline

acyclovir triphosphate

active metabolite of acyclovir

4-hydroxycyclophosphamide

active metabolite of cyclophosphamide

cyclophosphamide

• designed to mask the toxic side effects of its active metabolite

ampicillin

active metabolite of hetacillin

hetacillin

• designed to increase the chemical stability of the active metabolite

carbenicillin

active metabolite of carbenicillin indanyl sodium

phase I metabolism

• generally tends to provide a functional group or “handle” to the molecule

• a new functional group introduced into the drug molecule or an existing functional group is modified making the drug more polar and more readily excreted

• deactivation

• activation

• intoxication

• altered pharmacologic activity

possible results of phase 1 metabolism

deactivation

decreased pharmacologic activity

activation

increased pharmacologic activity

intoxication

increased toxicity

n-demethylation

morphine → normorphine

dealkylation

iproniazid → isoniazid

isomerization

retinoic acid → 9-cis-retinoic acid

normorphine

• has about one-fourth as active as morphine in producing analgesia but has a much lower physical dependence capacity

retinoic acid

acne tx, psoriasis

alitretinoin (9-cis-retinoic acid)

for eczema, sarcoma

isotretinoin (13-cis-retinoic acid)

cystic acne tx, neuroblastoma

oxidation

• most common phase 1 of biotransformation

• vast majority of this is catalyzed by a group or mixed function oxidases known as CYP450

• acetaminophen

• fluoroquinolones

• imipramine

• theophylline

these are metabolized by CYP1A

prostaglandin

metabolized by CYP4B

cyp2d6

responsible for genetic polymorphism

cyp3a4

most important cyp 450 isozyme

oxidative reactions

• olefins - carbamazepine

• alcohols and aldehydes

• aromatic moieties

aromatic hydroxylation

• phenylbutazone to oxybutazone

• aniline to p-aminophenol (NADPH-dependent oxidative reactions)

deamination

• amphetamine to phenylacetone

desulfuration

• thiopental to pentobarbital

reduction

• it has same goal as oxidation reaction to create polar functional groups that can be easily excreted

• bacteria resident in the GI tract are also responsible for reductions of azo and nitro groups

carbonyl reduction

• aldehyde reduction

• ketone reduction

aldehyde reduction

• chloral hydrate to trichloroethanol

• acetohexamide

ketone reduction

• prednisone to prednisolone

azo reduction

sulfasalazine

nitro reduction

chloramphenicol