midterm one memorize Flashcards
(114 cards)
1
Q
Pka <2
A
strong acid
2
Q
pKa 4-6
A
wA, weak conj base
3
Q
pKa 8-10
A
very weak acid, strong conjugate base
4
Q
pKa>12
A
no acidic properties
strong conjugate base
5
Q
what form of A or B has better absorption
A
unionized
6
Q
Stomach conditions pH bases acids surface
A
pH = ~2
Bases = protonated and charged
Acids = protonated and ucharged
surface +
7
Q
Intestine conditions pH Bases Acids Surface
A
pH = ~8
bases = unprotonated and uncharged
acids = unprotonated and charged
surface +++
8
Q
maximum water solubility when
A
ionic form of drug
9
Q
maximum lipid solubility when
A
unionized form
10
Q
when does pH=pKa
A
when 50% ionization of either basic or acidic drug
11
Q
what can exhibit both acidic and basic properties
A
Alcohols
12
Q
Acidic functional groups
A
- Carboxylic acids (RCOOH)
- Sulfonic acids (RSO3H)
- Phenols (Ar-OH)
- Amides (RCONHR) & imides (RCONHCOR)
- Sulfonamides (Ar-SO2NHR)
13
Q
basic functional groups
A
Basic functional groups
-Aliphatic amines (R1NH2, R2NH, R3N) -Aromatic amines (Ar-NH2) -Heterocyclic amines
-Alcohols (R-OH)
-R = Alkyl groups
-Ar = Aromatic rings
-Alcohols (R-OH):
Can exhibit both acidic and basic properties
14
Q
What order of basic strength NH3 primary amine secondary tertiary amine
A
NH3= least basic
primary amine most basic
tertiary amine least basic (of 1’ 2’ 3’)
15
Q
negative inductive effect
A
attract elections (EWG) -halogens
16
Q
positive inductive effect
A
push electrons away from self to rest of molecule (EDG)
17
Q
why is the inductive effect distance dependent
A
the inductive effect decreases with increasing number of bonds
18
Q
what is the inductive effect
A
measure of electrostatic phenomena caused by electron displacement along bonds
-transmitted along sigma bonds
19
Q
Electron donating groups (EDG-resonance): -OH, -NH2, -SH, -OR, -NHR, -SR
Electron withdrawing groups (EWG-resonance): -COOH, -CHO, -NO2, -CN, -CF3, -COR, - COOR, -OCOR -SO2R, -SO2NHR
EDG (inductive effect) : -CH3, -CH2R1, -CHR2, -CR3O-, -COO-
EWG (inductive effect): -F, -Cl, -Br, -I, -NH3+, -NR3+, -NO2, -COOH, -CN, -SO2R, -SO2NHR
A
study
20
Q
bioisosteres
A
atoms, func grps, structural elements, similar physical and chemical properties such that they produce similar biological activities
Maintain or enhance biological activity
enhance physiochemical properties
+better potency, absorption, side effect profile, duration of action, metabolic stability
21
Q
See slide 62-63 rings
A
asdfdsasdfadssdf
22
Q
SAR strategies
A
1) variation in substituents
2) extension of chemical structure
3) chain variation/extension/contractions
4) ring expansions/contractions
5) ring variation
6) bioisosteres
7) structure simplification - removal of substituents
8) adding stereochemical features - introduce R/S
23
Q
pharmacophore of ciprofloxacin
A
quinolone
24
Q
pharmacophore of cefuroxime
A
aminocephalosporanic acid
25
Ampicillin pharmacophore
aminopenicillanic acid
26
amantadine pharmacophore
adamantane
27
What is QSAR
quantitative structure-activity relationships
| -statistical/mathematical modelling to explain and or predict pharmacological/biological properties
28
linear regression coefficient of 1
r=1=perfect fit
29
2 types QSAR
2D-QSAR ---> considers only 2D-sturctures....classical QSAR
3D-QSAR ----> considers 3D structures
30
1962 - corwin hansch
developed SAR in plant growth regulators and their dependency on substituent effects
31
Major molecular descriptors in QSAR
1) lipophilicity parameters
+logP and pi
2)electronic parameters
+hammett constant
3) steric (size and shape) parameters (taft steric parameter Es and molar refractivityMR)
32
hydrophobicity substituent constant (pi)
values depend on aliphatic/aromatic parent molecule
-attached group and other groups already on molecule
values depend on solvent used to obtain partition coefficient values
pi=logPx - logPH
```
+pi = more lipophilic than H
-pi = less lipophilic than H
```
33
difference between logP and pi
logP measures overall hydrophobicity of molecule
pi measures hydrophobicity of specific region
34
what is pi used to calculate
the theoretical logP of derivatives
| -reduces need to synthesize
35
Hammetts constant
sigmax = log( Kx/KH) ; Kx = derivative, KH = parent
36
Hammett constant
| effect of EW substituent
shifts equilibrium right (to deprotonated benz acid)
37
Hammett constant
| effect of ED substituent
shifts equilibrium left (to protonated benz acid)
38
negative Hammett constant
EDG
39
positive Hammett constant
EWG
40
what is Hammett constant
sum of total resonance/inductive effects and the position of the substituent
(ortho meta para)
41
what effects dominate at para position
resonance
42
what dominates at meta-position
inductive
43
steric effects
shape and size of drug and physical dimensions of target site and bioactivity
44
what are the 3 steric effects
taft steric parameter (Es)
Molar refractivity (MR)
verloop steric parameter (bond angles, VDWradii, lond lengths)
45
Molar refractivity
measure of volume and polarizability of a molecule
high MR = high size/volume
46
Congeneric series
data set that provides accurate experimental measures of biological activity for a group of compounds
47
all drugs in a concentric series exert the same MoA
true
48
Hansch model
The n-octanol-water partition coefficient of drug molecules are additive molecular property that correlates with solubility properties of drug molecules (their transport and binding)
49
Physicochemical properties such as lipophilicity, electronic properties, polarizability and or steric parameters of substituents can be modeled into one equation to predict and describe drug-receptor interactions quantitatively
what model does this
Hansh
50
what does not play a major role in pharmacological activity
| -can be ommited from hansch model QSAR equation (3var --> 2var)
Steric effects do not play a major role in pharmacological activity
-MR can be ommited to make a 2 variable equation
51
what does a high log(1/C) mean
higher biological activity
52
3D Qsar
Important regions of bioactive molecules are mapped in 3D space,
regions of hydrophobicity, hydrophilicity, H-bonding acceptor, H-bond donor are rendered so that they overlap, and a general 3D pattern of the functionally significant regions of a drug are determined
53
Drawback of 3D QSAR
biological effect is produced by the model compounds/drugs
NOT BY A PRODRUG
54
3D QSAR
- data set
- how det bioactivity
- compounds
- data set of compounds that bind to the same active site/receptor
- bioactivity explained by thermodynamics of system (enthalpy)
- compounds exhibit similar conformation or binding mode
55
what is not considered in 3D QSAR
diffusion, solvent effects, transport processes
56
Computational methods in drug development
1) molecular dynamics/ molecular docking
- investigate drug receptor/protein interactions to dev new drugs
2) de novo design
- develop unknown receptor ligand relationships
3) Pharmacophore modeling
- used generate receptor ligand models (known and unknown)
57
what is "in silico"
computer simulation
58
CADD
computer assisted drug design
| -uses computational chemistry tools to discover new drug candidates (molecular modelling)
59
ligand based drug design
already looked at bioactive conformation
based on key features can you come up with own new drug molecule
60
Receptor based drug design
know 3D structure of target
-examine protein structure
design your drug based on lock and key
61
lipinski's rule of five
potential drug candidate should exhibit:
1) have 5 or less h-bond donors (sum of OH and NH groups present)
2) MW less than 500
3) logP less than or equal to 5
4) ten or less H-bond acceptors (sum of N and O)
62
pharmacophore modeling (3D-QSAR)
1) specifications of spacial arrangement of small number of atoms or groups of atoms or functional groups = pharmacophore
2) ID specific pharmacophore descriptors
3) 3D-QSAR obtain pharmacophore info to diverse class of compounds
4) search databases to find mols/cpds w/ sim pharmacophore 3D-fit
5) can be used to synth new molecules or obtain potential drug candidates
6) determines distance/bond angle/electron/charge distribution needed to develop a core ring template/scaffold with bioactivity
63
2D QSAR summary
- considers physiochemical properties of mols and their relationship to their biological activities
- now limited use bc advances 3D-QSAR and computational tools
- still used to predict toxicity parameters of new drugs
- still useful when target enz/protein/receptor is unknown or if x-ray/NMR data of target is unknown
64
3D QSAR
- used to design and develop new molecules to target known/unknown proteins and enzymes --->superior to 2D-QSAR
- used to study binding interactions mols with target enzs/proteins --> SAR optimization ---> optimization of drug candidates
- predict bioactivities of DIVERSE CLASS of molecule libraries, stereoisomers and mols with diff MoA
- considers 3D parameters and is useful predict binding modes and bioactivities of stereoisomers
65
enantiomer
mirror image
| -non superimposable
66
stereoisomer
cant be made equivalent by rotations about single bond
67
conformational isomers
can be made equivalent by rotation about a single bond
68
consitutional isomer
different bonding order
69
dextrorotatory "D" or (+)
rotates polarized light right, clockwise
70
levorotatory "L" or (-)
rotates light to left, counterclockwise
71
What replaced D/L nomenclature
R and S
- R = RH
- S = LH
72
what differences exhibited by enantiomers
differences in
- potency,
- receptor affinity
- biological activity
- transport
- metabolism
73
what is an equimolar mixture of a pair of enantiomers called. does it exhibit optical activity
- racemic mixture... no optical activity
74
naturally occuring AAs are pure enantiomers (chiral)
-single enantiomer
T/F
true
75
Cahn ingold
priority based off Atomic number
76
racemic mixtures represented by what bond line
wiggly bond lines
77
how many sterioisomers are possible
| -equation
n steriocenters has 2^n sterioisomers possible
BEWARE MESO COMPOUNDS
78
Enantiomers have identical physical and chemical properties
true
79
diasteriomers (not mirror images) have different physical properties
true
80
diasteriomers as result of restricted rotation
due to DBs or rigid ring systems
81
geometric isomers
due to restricted rotation about a C=C
82
Drugs exist in more than one conformation
| -receptor implication
-drug may bind to more than one receptor but a specific receptor sight may only bind one of many conformations of a drug
83
what does it mean to say:
| drug receptor/enzyme binding is stereospecific
only one confromation of drug can interact with AS
84
enantiomers and bioactivity
different enantiomers can have different potency or different pharmacological activity
ex. thalidomide
S - birth defects
R - sedative
85
Vit D3
| E vs Z
E - pharmacological activity - treat osteoporosis
z - no pharm act
86
Prodrugs
pharmacologically inactive compound converted to active drug by metabolic biotransformation
-prior during and after absorption or at specific target sites
87
prodrugs enhance (8)
- Solubility
- Absorption and distribution
- Site specificity
- Instability
- Prolonged release
- Toxicity
- Poor patient compliance, eg: oral vs injection
- Formulation issues
88
carrier linked prodrugs
group that can be easily removed enzymatically (such as an ester) to reveal the true drug
ex.tamiflu and loratadine
89
bioprecursor prodrug
metabolized into new compound that may be active or further metabolized to an active form
ex. aciclovir
90
Alcohol containing drugs linked as esters
esters easily hydrolyzed by esterases in vivo to form active metabolite
esters readily synthesized from an alcohol containing drug
ex. drug-OOR ---> drug-OH + HOCOR
91
carbozylic acid containing drugs linked as esters
esters readily hydrolyzed in vivo to form active metabolite
esters readily synthesized from COOH containing drug product
92
Amine containing drugs (linked as amides)
amides readily hydrolyzed by amidases in vivo to form active metabolite
93
selective ion channel
one or two ions
94
non-selective ion channel
multiple ions to pass
95
to types of ion channels
voltage gated
| ligand gated
96
ion channel makeup
one large protein with multiple domains
OR
multi subunit complezes
97
Pharmacokinetics
what the body does to the drug
| -ADME
98
pharmacodynamics
what the drug does to the body
| -conc/time profile and AE/therapeutic effect
99
ADME
```
PHARMACOKINETICS
absoption
distribution
metabolism
excretion
```
ONSET OF DRUG ACTIVITY, DURATION AND INTENSITY
100
WHAT IS THE FASTEST RoA
IV
| -goes straight to plasma
101
oral or rectal RoA
gut -----> feces
- ---->plasma
- ---> liver ----> kidney--->urine
liver-->bile-->gut
102
from plasma where can drug go
in and out of tissues
| -diffusion and AT
103
plasma conc vs time curve
plasma conc rise in body
-predominantly absorption from GI tract
absolute maxima
-combined ADE
plasma conc dec
-predominantly hepatic or renal elimination
104
how are most drugs administered
orally
105
where are orally administered drugs absorbed
GI tract
106
requirements for orally administered drug be absorbed in GI tract
1) dosage form allow drug become dissolved in aq medium
2) drug itself = weak acid or base needs be sufficiently hydrophillic to dissolve in water
3) once dissolved drug needs be hydrophobic enough passively diffuse across epithelial cell membrane
- some cases AT by carrier protein
107
bioavailability
- what reflect
- relative to what
represents amount of uncharged parent drug that reaches systemic circulation
always relative to another RoA, almost always rel to IV injection
108
almost all drugs are what
wA or wB
109
esophagus pH
~7
110
stomach pH
as low as 2
111
SI pH
~8
112
how many halflives until drug considered out of system
7
113
protein kinase what does it phosphorylate
serine
threonine
tyrosine
(uses ATP)
114
RTK typically termed what
growth factor receptors
