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By adding or removing functional groups to a drug you change the?
physicochemical properties of a drug
acid-base properties, water solubility partion coefficient, crystal structure stereochemistry are all example of what
changing the physicochemical properties of a drug can affect what of a drug
toxicity and Pharmacokinetics ADME
changing functional groups changes solubility with in trun changes how the body works on the drug
Most drugs act on receptors by binding to them making them
structurally specific
Drugs can be classified as being structurally specific or structurally nonspecific. Structurally
specific drugs, which most drugs are, act at specific sites, such as a receptor or an enzyme. Their activity and potency are very susceptible to small changes in chemical structure;
molecules with similar biological activities tend to have common structural features.
Structurally nonspecific drugs have no specific site of action and usually have lower potency.
?? approaches are used when the structure of the target receptor is known
direct design
approaches are used when the receptor structure is not known.
indirect design
the lock and key model of fischer explains what
the better the complementary fit of the drug to the receptor, the more potent the drug will be.
the structure of the receptor (either X-ray crystal structure or
NMR solution structure) should be known; then, different drug analogs can be docked into
the receptor.
the induced fit model proposes
that a suitable ligand will beable to induces the receptor and produces a normal effect while if it is not suitable it will not beable to produce an effect
which phase is generally a few months to a year and a half and evaluates the safety, tolerability (dosage levels adn side effects),pharmacokinetic
properties, and pharmacological effects in 20–100 healthy volunteers
phase I
(about 1–3
years) assesses the effectiveness of the drug, determines side effects and other safety aspects,
and clarifies the dosing regimen in a few hundred diseased patients;
phase II
(about 2–6
years) is a larger trial with several thousand patients in clinics and hospitals that establishes
the efficacy of the drug and monitors adverse reactions from long-term use.
phase III
considered to be the results found with a drug that has already been allowed onto the drug
market and is in general use
phase IV
Once the new
drug application (NDA) is submitted to the Food and Drug Administration (FDA), it can be
several months to several years before it is approved for commercial use because they are reviewing what? When is it filed
filed with the FDA at the conclusion of phase III trials. they analyze the datat from medical reveiw, bipharmaceutical, statistical, pharmacolog, chemistry, microbiology studies.
The FDA gets the final decsion of approval what are some things they can do when the NDA is filed
grant full or partial approval, limit the request of uses, add warnings or contra indication, may only approve for certain patients
another name for a Drug candidates is
(or new chemical entities, NCE
why do drugs cost so much to purchase
to recover the financial losses for the company on all teh failed drugs. it is not that it cost that much to manufacture
In general drugs are not discovered but what is more likely discovered is known as
a lead compound
what is a lead compound
a prototype compound that has a number of attractive characteristics,
such as the desired biological or pharmacological activity, but may have other undesirable
characteristics, for example, high toxicity, other biological activities, absorption difficulties,
insolubility, or metabolism problems.
why do we modify the lead compound
to amplify the desired activty and to minimize or eliminated the unwanted properties to a point where a drug candidate is identified
a compound worthy of extensive biological, pharmacological, and animal studies is a
drug candidate
a compound ready for clinical trials is
a clinical drug
drug discovery without a lead are relatively (many or few)
few in number
the ticpical occurrence of drug discovery is that
a lead compound is identified, and its strucuture is modified to give, eventually the compound that goes to the clinic
what is the initial difficulty in drug discovery
finding the lead compound
what approaches can be taken to identify a lead
have means to assay the compond for activity, what is the relative activity to a control compound, does it have the desired effect, and what the potency is
what is the difference b/w activity and potency
activity is the particular biological or pharmacological effect while potency is the strength of that effect
what was invented to screen robotically a large amount of compound's activity against sensitive in vitro assay
HTS high-throughput screens
( compound screening also can be carried out by electrospray ionization mass spectrometry and by NMR
what can supply huge nubmers or compounds in a short period of time which theoretically should provide an increased number of hits
combinatorial chemistry
by screening compounds and looking for the buildup of an intermediate it is possible to
identify compounds that block the pathway and to determine which enzyme is blocked
once a screen is developed what approaches can be taken to obtain a lead
use the natural ligand for a receptor as the lead compound or use a drug already marketed
what kind of screening involves no intellectualization; all compounds are
tested in the bioassay without regard to their structures. this was essentially the only approach prior to 1935 or the discovery of sulfa
Random screening
An example of a random screen of synthetic and natural
compounds was the “war on cancer” declared by Congress. no longer done because of budget issues
The two major classes of materials screened
are synthetic chemicals and natural products
(microbial, plant, and marine
two important antibiotics, streptomycin and the tetracyclines, were found this way
____is a more narrow approach
than is random screening.
compounds having a vague resemblance to weakly
active compounds uncovered in a random screen, or compounds containing different
functional groups than leads, may be tested selectively
also called targeted or focused screening,
also called targeted or focused screening,
The affinity of the ligand or a small molecule that binds to a receptor
can be measured by varying the collision energy and determining at what energy the complex dissociates. by varying the collision energy, it is possible to determine which test molecules bind to teh biolmolecule best
what do we do drug metabolism studies
to determine if the activity ovserved is dervied from the drug candidate or from a metabolite. metabolites can be screened for other activities as well
What can sometimes be found by clinical observations
that the drug candidate will exhibit more than one pharmacological activty; that is, it may produce a side effect.
dramamine-antihistamine-seasickness
bupropion-depression smoking cessation. viagra-angina ED
name all the non rational approaches to lead discovery
random screening, nonrandom, drug metabolism studies, and clinical observations
the lead is just found by screening techniques, as a by-product of drug metabolism studies or from clinical investigations
Is is possible to design a compound having a particular activity? what would the fist step be
yes, the rational approaches to drug design now have become the major routes to lead discovery. The first step is to identify the cause for the disease state
once the relevant biochemical system is identified, what becomes the lead compound
the natural receptor ligands or enzyme substrates
true or false
it is not possible with much accuracy to foretell toxicity and side effects, anticipate transport characteristics, or predict teh metabolic fate of a drug
True. page 17
once you have a lead compound, how do you know what to modify in order to improve the desired pharmacological properties
interactions of drugs with receptors are very specific and only a small part of the lead compound may be involved in the appropiate recepotr interactions. The relevant groups on the molecule that interacts with the receptor adn are responsible for the activity are collectively known as the pharmacophore are not usually modified. Everything else (auxophore) can be modified to enhance the properties
you will know which groups must be excised and which you can retain or modify as needed.
why is it important to know what is part of the pharmacophoric groups and what is the auxophore
need to know what is eesential to maintain integrity of the molecule adn hold in postition, need to know what may be interfering with binding, as well as those not just in case you to modify to enhance other fxn without loss of potency
modifications of the atom not interfering with binding could be very important to solving pharmacokinetics problems
one approach in lead modification to help distinguish active parts from non active parts of the molecule is to
cut away sections of the lead molecule and measure the effects of those modifications on potency
when excising a group that affects the compound by decreasing its potency will tell you what about that group
that it may have been pharmacophoric
when excising a group that affects the compound by incrasing the potency will tell you what about that group
that it was auxophoric and interferring with proper binding
when excising a group that doesn't change the potency means
that it was auxophoric but not interfering with binding
the goal to modifications of the lead compound is
both incrase potency and decrease adverse effects such as addictive properties
by cutting pieces off of the lead compound
it gives you new perspective on possible active structures
what if every cut in the lead produces a compound with lower potency?
then either every excision is removing part of the pharmacophore or each cut causes a conformational change that gives a structure less similar to the bioactive conformation.
the later possibility is particularly relevant to such a rigid compound as in morphine where groups need to be added to the lead structure to increase teh pharmacophore
the activity and potency of a molecule are related to
the interactions of the pharmacophoric groups with groups on teh receptor
average binding energies can be used to
determine how well a new molecule binds to its receptor
if the test molecule has a measured binding energy that is lower than the calculated average value what does it suggest
that the molecule contains groups that do not interact with the receptor and therefor can be excised without loss of potency, giving a simplied lead for further structural modification
the reason for functional group modification is that a
relationship exists between the molecular structure of a compound and its activity. By modifing the groups, we can modify the activity
the physiological action of molecure is a ____ and was determined from its structure-activy relaitonships
a function of its chemical constitution
which drugs act at specific sites such as receptor or enzyme. their activity and potency are very susceptible to small changes in chemical structure.
structurally specific drugs
molecules with similar biolgical activites tend to have
common structural features
what type of drug has no specific site of action adn usually have lower potency. Also a variety of other structures can produce similar biological activities
structually nonspecific drugs
the hallmark of SAR studies is to synthesis and test as many analogs as possible and determine the effect of
structure on activity or potency
what is usually the guide for chosing analogs made
ease of synthesis, rather than cogent rationales, is often the guiding force behind the choice of analogs made
electronegative groups on benzene ring can be
Cl, CF3, NHR
after large number of modificaitons are introduced to the lead compound what conclusion can be made
SAR or actually, structure-potency relationship
a common way to track the structural changes is with the use of
molecular activty maps
what are structural drawing of a lead compound annotated to show where in the molecule specific structural changes affect activity or potency measure in a single bioassay
molecular activity maps
what can molecular maps show/do
long lasting drug discovery efforts involving many chemist, can prevent coworks form systhesizing analogs that have already been made and tested, adn tehy may direct the chemists' creativity to unexplored regions of the lead compound yielding novel structual changes
does each structure interact with only one recetor and to only one activty
no there are things called privileged structures adn for certain molecular scaffold that appear to be capable of binding to multiple receptor targets adn consequently with appropriate modificaiton could exhibit multiple activities
SAR by NMR was developed to screen libraries of what?
small organic molecules and to identify and optimize high affinity ligands
many of the bonds that hold the drug to the target are relative weak so how do they stay in place
hey have additive properties
ionic, hydrogen, dipole-dipole, van der waals hydrophobic
what are two objective of medicinal chemists
what functional groups are important for pharmacological activity and how to modify these functional groups to produce more potent, selective and safer drugs
screening methods for biological activity
bioassays, high throughput screening
two opproches for the identification of a hit/lead compound
compound or target centered approach
things you can do for structure modicfications to increase potency adn therapeutic index is
homologation, chain branching, ring chain transformation, non classical and classical bioisoterism
structure modificiations to increase oral bioavailablity are
electronic effects, and effects of lipophilicity and ionization
What are some quantitative structure activty relationships
steric effects and methods used to correlate physicochemical parameters with biological activity: topliss and craig plot
what are some advantages of obtaining drugs from nature
reasonable likelihood of activity, easier to isolate than to synthesize because of their complex structures, can be used as starting point for semi-synthetic drug
natural products
seem to provide greater structural diversity than standard combinatorial chemistry,natural products that are biologically active in assays generally have drug-like
properties, i.e., are capable of being absorbed and metabolized.Generally the excessive time taken to isolate and characterize bioactive compounds from natural
product extracts is a disadvantage of the method, but the reward may be greater molecular
diversity, which gives the greatest opportunity to identify a variety of scaffolds for screening.
what are some disadvantages of obtaining drugs from nature
no gurantee of success, takes significant effort to isolate them, and difficult to determine the test system for biological activity
semi-synthetic drugs are an active natural product tha is modifited chemically to improve pharmacological profiles adn reduce toxicity/side effects such as
increase oral bioavailability, increase potency/selectivity, increase duration of action, increase effectiveness,and reduce toxicity/side effects
The electronic parameter, σ, depends on the
electronic properties and position of the substituent
on the ring and, therefore, is also called the substituent constant.
The more electron
withdrawing a substituent, the more
positive its σ value (relative to H, which is set at 0.0);
conversely, the more electron donating, the more negative its σ value.
The meta σ constants
result from ,
inductive effects
the para σ constants correspond to the
net inductive and
resonance effects. Therefore, σ meta and σpara for the same substituent, generally, are not the
same.
if a drug has a problem with oral bioavailabilty it is likely because it
has low water solubility or high lipophilicity. low lipophilicity is typically more of a problem,
because that leads to poor permeability through membranes
highly lipophilic compounds also are
easily metabolized or bind to plasma proteins
The more electron
withdrawing a substituent, the more ---- its σ value
positive
the more electron donating, the more ---- its σ value.
negative
The ρ values (the slope) depend on the particular type of reaction and the reaction conditions
(e.g., temperature and solvent) and, therefore, are called
reaction constants. The
importance of ρ is that it is a measure of the sensitivity of the reaction to the electronic
effects of the meta- and para-substituents
Reactions that are favored by electron donation in the
transition state (such as reactions that proceed via carbocation intermediates) have negative ρ
values and there for ---slopes
(i.e., the linear free-energy relationship has a negative slope);
reactions that are aided by
electron withdrawal (such as reactions that proceed via carbanion intermediates) have -----ρ values.
positive
if a compound is more soluble in water than
in 1-octanol, then its p value will be
P <1, and, therefore, log P is negative
a molecule more soluble
in 1-octanol has a P
>1, and the log P is positive
the more positive the log P,
the more
lipophilic it is
The larger the value of P, the more there will be an interaction
of the drug with the
lipid phase (i.e., membranes).
As P approaches zero, the drug will be so water soluble that
it will not be capable of
crossing the lipid phase and will localize in the aqueous phase
there will be a value of P such that drugs having this value will be least hindered
in their journey through macromolecules to their site of action. This value is called
log P0,
the logarithm of the optimum partition coefficient for biological activity
the log P0 generally
occurs in the range of
5-9 carbon atoms
If a
lead compound has modest CNS activity and has a log P value of 0, it would be reasonable
to synthesize an analog with a ---- log P.
higher
Because of the problem associated with ionization of compounds, which leads to greater
water solubility than predicted from the neutral structure, often the term logD (the log of the
distribution coefficient, generally between 1-octanol and aqueous buffer) is used to describe
the
lipophilicity of an ionizable compound
Because ionization is a function of the pKa
of the compound and the pH of the solution in which the compound is dissolved, log D
describes the
log P of an ionizable compound at a particular pH.
Delocalization of nonbonded electrons into aromatic systems decreases their
availability for hydrogen bonding with the aqueous phase and,
therefore, increases the π.
Inductive effects are quite important to lipophilicity. In general, electron-withdrawing
groups increase
π when a hydrogen-bonding group is involved.
The electron-withdrawing inductive effects of the phenyl group make the nonbonded electrons on the OH group less available for hydrogen bonding, thereby
reducing the affinity of this functional group for the aqueous phase
Steric effects are variable. If a group sterically shields nonbonded electrons, then aqueous interactions will decrease, and the π value will increase. However, crowding of functional groups involved in hydrophobic interactions will
have the opposite effect.
How is it possible to design a compound that is neutral when it needs to cross
membranes, but ionized when it finally reaches the target receptor?
This is possible because
an equilibrium is established between the neutral and ionized form of a molecule or group
that depends on the pH of the medium and the pKa of the ionizable group.When the pH of the medium equals the pKa of the molecule, half of the molecules are in
the neutral form and half in the ionized form.The ones that are neutral may be able to cross
membranes, but once on the other side, the equilibrium with the ionized form is reestablished
(the equilibrium mixture will again depend on the pH on the other side of the membrane), so
there are now ionized molecules on the other side of the membrane that can interact with the
target receptor. The ionized molecules that did not cross the membrane also reestablish an
equilibrium and become a mixture of ionized and neutral molecules, so more neutral molecules
can get across the membrane.
all would theorectically get across if it wasn't for metabolism and excretion
To adjust the ionization equilibrium of the lead compound, you need
to add electron-withdrawing or electron-donating groups to vary the pKa of the molecule.
Electron-withdrawing groups will lower the pKa, making
acids more ionizable and bases less
ionizable; the opposite holds for electron-donating groups.
In general, they concluded that if the molecular
weight, the degree of branching, the number of rotatable bonds, or the number of hydrogen
bond acceptors is increased, the compound will be
less likely to be CNS active
If the aromatic
density, number of hydrogen bond donors, or log P is increased, the compound is
more likely
to be CNS active.
Because many systems are+π dependent,
that is, the potency increases with increasing π values, then a good choice for your first analog
would be one with a substituent having
a +π value.
Because π4-Cl =0.71 and σ4-Cl = 0.23 the 4-chloro analog (2.91, R = Cl) should be synthesized and
tested. If it is more potent,
then it can be attributed to
a +π effect, a +σ effect, or to both.
To determine which is
important, one term could be held more or less constant and the other varied. For example, the
4-phenylthio analog (π4-PhS = 2.32, σ4-PhS = 0.18) would be a good test of the importance
of lipophilicity, and the 4-trifluoromethyl analog (π4-CF3 = 0.88, σ4-CF3 = 0.54) would test
the importance of electron withdrawal.
What if the 4-chloro analog was equipotent with the parent compound? This could result
from a favorable +π effect counterbalanced by an unfavorable +σ effect or vice versa.
If this
is the case, then the 4-methyl analog (π4-Me = 0.56, σ4-Me = −0.17) should show enhanced
potency. Enhancement of potency by the 4-methyl analog would suggest that the synthesis of analogs with increasing π values and decreasing σ values would be propitious.
If the 4-
methyl analog is worse than the 4-chloro analog, perhaps the equipotency of the 4-chloro
compound was the result of a favorable σ effect and an unfavorable π effect. If the 4-chloro analog was less potent than the lead, then there may be a steric problem
at the 4 position or increased potency depends on −π and −σ values.
Thus, if both the π and σ terms have positive
coefficients, then substituents in the upper right-hand quadrant of the plot (Figure 2.17) should
be selected for future analogs.
craig plot
A variety of approaches can be taken to utilize molecular modeling for drug design;
----approaches are used when the structure of the target receptor is known
direct design
---- design approaches are used when the receptor structure is not known.
indirect
The basic
premise in the utilization of molecular graphics is that the better the complementary fit of the
drug to the receptor, ---
the more potent the drug will be