MED CHEM Flashcards
1
Q
Lipinski Rule of 5
A
poor absorption if cLogP>5 MWt>500 no. of H bond donors >5 no. of H bond acceptors > 10
2
Q
oral bioavailability
A
measure of degree to which a drug reaches systemic circulation following oral dosing F%
3
Q
equation for oral bioavailiabilty
A
AUCoral/AUCiv x Doseiv/Doseoral x 100
4
Q
relationship between half life volume and clearance in minutes
A
T1/2 = 0.693 x Vd(mL/Kg)/Cl(mL/min/Kg)
5
Q
A
6
Q
relationship between half life volume and clearance in hours
A
T1/2 = 12 x Vd(L/Kg)/Cl(mL/min/Kg)
7
Q
What is Clearance
A
volume of blood cleared of drug per unit time want low
8
Q
liver blood flow rate
A
20ml/min/kg
9
Q
Kidney blood flow rate
A
2ml/min/kg
10
Q
How to tell if clearance is renal or hepatic
A
renal logD7.4<0 hepatic logD7.4>0
11
Q
Pharmacodynamics
A
study of pharmacological response to a drug, potency, selectivity what the drug does to the body
12
Q
Pharamcokinetics
A
movement of a drug through the body
ADME simply: what the body does to the drug
13
Q
lipophlic log P
A
postive
14
Q
polar log P
A
negative
15
Q
log P Me
A
0.5
16
Q
Et
A
1
17
Q
Cl
A
0.7
18
Q
CF3
A
0.9
19
Q
pH
A
1.9
20
Q
F
A
0.15
21
Q
H
A
0
22
Q
CN
A
-0.5
23
Q
CONH2
A
-1.4
24
Q
SO2NH2
A
-1.8
25
SO2Me
-1.6
26
What is Ligand efficiency
free binding energy per heavy atom measure how well compound binds relative to size (Kcalmol^-1/heavy atom)
27
equation for ligand efficiency
-RTlnKi/HAC -1.4log(IC50)/HAC <0.2 = poor 0.3 = satisfactory >0.4 high
28
polarity
measure of how hydrophilic a compound is
29
polar compound selectivity
good
30
polar compound solubility
good
31
polar compound safety
good
32
polar compounds stability
good metabolic stability
33
polar compound half life
short
34
polar compound absorption
poor transcellular absorption from gut
35
polar compound VoD
short
36
ionisation
measure of degree to which compound charged under physiological conditions
37
solubility in gut for positively charged
good solubility in gut slightly acidic
38
positively charged VoD
high volume of distribution
39
positive absorption
reduced absorption
40
positive charged safety
ion channel based safety issues
41
negative charged compound solubility
improved solubility
42
negative charged compound
low VoD
43
negative charged compound absorption
reduced absorption
44
negative charged compound safety
good safety
45
negative charged compound selectivity
good selectivity
46
Drug Binding
Drug + protein <-> drug protein complex (Keq)
47
Drug dissociation
Drug Protein complex <-> Drug + Protein (Ki or Kd) ( greater affinity of drug for protein smaller KI)
48
IC50
concentration of drug required to inhibit the protein of block binding to the protein by 50%
49
Hit
compound confirmed activity 5-0.5 microMolar against larger get protein activity with structurally relevant compounds may be confirmed
50
Candidate
single compound from lead series meets all minimum requirements for progress towards development
51
Lead
compound with potential to progress full drug
52
LogP
log( [Drug]octanol/[non ionised drug]water)
53
Log D
Log D (usually measure at ph7.4) = log ([drug]octanol/[ionised and non ionised drug]water)
54
What is lipophilicity
measure of how greasy a compound is
55
examples of lipophilic compounds
aliphatic chains aromatics halogen
56
Lipophilic compound selectivity
poor selectivity
57
lipophilic compound solubility
poor solubility
58
lipophilic compound stability
rapid removal metabolic instability
59
What do you need lipophilicity for
transcellular absorption from gut VoD efficacy half life
60
ligand lipophilicity efficiency
LiPE = - log(IC50) - clogP
61
What is lipophilicity efficiency
measure of degree to which potency is driven by factors other than lipophilicity
62
Base fraction unionised
1/(1+10^(pKa-pH))
63
base fraction ionised
1/(1+10^(pH-pKa))
64
Henderson Hasselbalch equation bases
pH = pKa + log10([B]/[BH+])
65
acid fraction unionised
1/(1+10^(pH-pKa))
66
acid fraction ionised
1/(1+10^(pKa-pH))
67
Henderson Hasselbalch acid
pH= pKa+ log10([A-]/[HA])
68
pKa + pKb
14
69
Kb x Ka
Kw
70
neutral compounds log P and D
log P = log D
71
log D and fraction
log D = log P + log ( fraction unionised)
72
Acids if pH-pKa>1
log D acids = logP +pKa -pH
73
Bases if pKa – pH>1
log D bases = logP -pKa +pH
74
Acid dissociation rule
pHpKa +2 acid approx. 99% dissociated >99% ionised
75
Base dissociation rule
pH99% ionised
pH = pKa-1 BH+ approx. 10% dissociated approx. 90% ionised
pH = pKa BH+ approx. 50 % dissociated approx. 50% ionised
pH = pKa+1 BH+ approx.90% dissociated approx. 10% ionised
pH>pKa +2 BH+ > 99% dissociated <1% ionised
76
Volume of Distribution
volume required to hold all drug added to the system at the same concentration to that measured in circulating blood compartment ( how well drug distributes out of blood into tissues) L or L/Kg
77
bases
molecule which can gain proton from water
78
zwitterion
molecule with acidic and basic functional group
79
acid
molecule which can lose a proton to water
80
How to maximise oral bioavailability
minimise dose cost waste toxicity risk interpatient variability
81
drug 1/2 life
time taken for drug plasma conentration to reduce by 50%
82
more lipophilic
more toxicity
83
less lipophilic
less toxicity
84
Ka acid
[H3O+][A-]/ [HA] = 55.5Keq
85
Kb basic
[BH+][OH-]/[B] = 55.5Keq
86
less ionised compounds
closer log P and log D are
87
neutral compound examples
carboxamides heteroatomics sulphonamides ketones ethers alcohol
88
Phase 2 metabolism
glucurodination (COOH alcohol phenol amine)
sulfation ( alcohol phenol amine)
Glutathione conjugation gly-cys-gly ( Halo-cpds epoxides arene oxides quinone-imine) make conjugated product
89
Phase 1 metabolism
* Oxidation
- Aliphatic or aromatic hydroxylation
- N-, or S-oxidation
- N-, O-, S-dealkylation
* Reduction
- Nitro reduction to hydroxylamine/ amine
- Carbonyl reduction to alcohol
* Hydrolysis
- Ester, amide or phosphate to acid and alcohol or amine
- Hydrazides to acid and substituted hydrazine ( can cause toxicity) metabolite
90
block metabolism by
adding fluorine to get rid of metabolic susceptibility of C-H
91
VoD and lipophilicity
VoD increases with increasing lipophilicity
92
acidic VoD
0.2 -2 L/Kg majority of drug withing total body of water cellular penetration limited
93
Basic VoD
0.5-30 favourable interaction between positive charge on drug and negatively charge phospholipid bilayer of cellular membrane
94
Absorption
– process whereby drug moves from site of administration into the body
– for oral drugs, this means crossing the gastro-intestinal tract
95
Distribution
– reversible transfer of drug from site of measurement (i.e. blood / plasma) into
other tissues
96
Metabolism
– process by which the body modifies drugs to make them more easily excreted
97
Excretion
– irreversible transfer of drug from site of measurement (e.g. blood / plasma)
– majority of excretion usually occurs via the urine or faeces
98
log P
measure of lipophilicity under non ionised condtions
99
logD
measure of lipophilicity under physiological conditions
100
log D same as log P
as long as pKa not change
101
predicting log P
The fragment logP values are used collectively in algorithms giving clogP Unusual' functional groups poorly parameterised and clogP may be misleading.
102
Drug discovery process
Disease and pathway -> target selection -> hit identification -> hit to lead -> lead optimisation ( identify clinical candidate) -> scale up clinical trials
103
How and when compounds die
Preclinical Animal toxicity, chemical stability
Phase 1 Human pharmacokinetics, toleration
Phase 2 Efficacy, safety, differentiation, dose size, cost
Phase 3 Long-term safety Non-approval
104
How long does it take to get a drug to market
10-15 years
105
How much does it cost to get a drug to market
1-2 billion
106
How many compounds does it take to get 1 drug to market
20-30 years
107
what type of druggable targets are there
kinases GPCRs and ion channels
108
hERG potassium ion channels
blocks to prolong QT causing Sudden Death (Torsade dePoints)
109
CYP450s
Main class of proteins involved in Phase 1 metabolism:
*
* Potential for drug-drug interactions
* A drug (or metabolite) with CYP inhibitor activity can affect its
own metabolism or the metabolism of co-administered drugs
* Carry out Phase I oxidations in liver cells (also present in the intestine)
* Membrane-bound Haeme-containing proteins coordinating FeII/III at
the active site
110
CYP450 reaction
React by abstracting H radical from the substrate; Weaker C-H bonds that leave stable
radicals most likely to be abstracted They are proteins with defined active sites; the
substrate must bind (in the correct orientation) hence not all ‘activated’ positions will be
metabolised.
111
How do we select targets
* Find biological targets (a protein or gene) that link to a disease
– Functional or structural information related to known targets
– Screen against compound collections
– Proteomics
– RNA interference
112
gibbs binding
- ΔGbinding = -RT ln (Keq) = RT ln (Ki)
113
base graph
log D against pka linear than flat level off to log P of ionised
flat log D = log P at top
linear log D = logP – pKa + 7.4
114
acid graph
flat then linear
Acids at pH 7.4 flat log D = log P no ionisation Linear log D = log P +pKa -7.4 End level off to lower limit logP of ionised
115
target validation
* Studies to build confidence that it is an appropriate target for the indication
* Efficacy
* Safety
* Differentiation
* Genetic knock-out, knock-down
* In vivo models
* Tissue distribution of target
* Biomarkers
* Ultimate test is in patients
* Key decision – target remains unchanged through the lifetime of the project.
116
Drug development process
Formulation – scale up toxicology Preclinical safety evaluation in animals – clinical studies phase 1 safety in a small group of human volunteers
clinical studies phase 2 ( 75% die) safety and efficacy in small group of patients
clinical studies phase 3 Large trial to assess safety and efficacy relative to existing treatments -
approval and launch Presentation of full data package to regulatory
117
CYPs interact stronger
more lipophilic substrates
118
log D and clearance
correlation between LogD and clearance LogD>3 then reducing LogD is likely to reduce clearance
Indeed when LogD>3, blocking metabolism at the most susceptible position
often just moves the site of metabolism to another part of the molecule.
119
druggable and less druggable compounds
Good surface contact achievable only with relatively large molecule = “less drugable”
Good surface contact achieved with a relatively compact molecule = “Drugable”
120
acidic e- donating and withdrawing
e- donating reduce acidity (destabilise resultant negative charge after deprotonation)
e- withdrawing increase acidity ( stabilise resultant negative after deprotonation)
121
basic group donating and withdrawing
e- donating R group increase basicity (CH3) ( lone pair on N more available stabilises resultant positive charge after protonation)
e- withdrawing R group reduce basicity ( benzene ketone ether) (lone pair less available destabilise resultant positive after protonation)
122
Target/mechanism types opportunities and issues
* Receptor agonists
* Ligand-gated ion channels (ionotropic receptors)
* Central targets
* Protein-protein interactions
* Irreversible inhibitors
* Dual pharmacology
* Combination therapy
* Antibodies
* Antiviral drugs
* RNA interference
* Protein degraders (e.g. PROTACs)
123
safety issues
cardiac ion channels with lipophilic bases safety issues anilines and nitro have higher toxicology risks
124
How to find hit to lead compounds
– From natural products
– From screening (high throughput, directed, fragments, virtual) and from existing drugs
directed
Some knowledge of the target/ligands
Smaller libraries
Higher likelihood of activity
Lower structural diversity
Fragments
MW ca 200
Enhanced hit rate*
Structural information required for follow-up
Highly sensitive detection (mM activity)
High quality fragment library required
High diversity of resulting leads
virtual
Ligand-based or target based
False positives
Relatively cheap and quick
Access to hit compounds
required for confirmation
125
For neutral compounds
log D = log P
126
for more ionised compounds
greater difference between log P and log D ionised component partition in aqueous layer redicing P for ionised log D lower than log P reflecting degree of ionisation
127
D
distribution coefficient
128
P
partition coefficient
129
pKa of amino pyridines
5-9
130
pKa of aliphatic amines
7-11
131
pKa of phenol
9-10
132
pKa of carboxylic acids
3-5
133
oral bioavailability and clearance
F% = 100 x Fabs x Fgut x Fhepatic
* F% related to total clearance (if route of clearance is hepatic)
* If 100% absorbed, no gut metabolism and exclusively hepatic
clearance, then F% = 1- Cl/Q x 100 (where Q is hepatic blood flow)
134
size and structural complexity
* The smaller the compound, the more room there is to enhance properties through addition = more Ligand efficiency
* MW<500 for orally absorbed compounds
* Small compounds less lipophilicity for good absorption but less selective
* Synthetic accessibility/ease of modification accelerate the follow-up programme
* Presence of stereogenic centres/sp3 character can help with selectivity but can add complexity to the synthetic programme
135
compounds that drive potency through polar interactions
high values of LiPE
136
nM potency
LiPE 5-7
137
compartment model
Kel = elimination rate constant
Time (h)
Plasma conc. (ng/ml)
C = C0 e-kel t First order rate kinetics
-dC/dt = Kel x C
log plot is a straight line
slope = -Kel / ln 10
138
more polar excreted product
renal excretion urine
139
less polar excreted compound
biliary excretion faeces
140
poly pharmacology
lack of selectivity for other targets lead optimisation much more challenging multiple SARs complicates biological profiling
141
Drug absorption
* Passive transcellular absorption most common route
– LogD>0 for transcellular absorption
– solvation and ionisation hinder
– interplay of solubility and dose size
* Need to avoid recognition by efflux pumps – such as P-glycoprotein (PgP)
142
Potency and ligand efficiency
* An indication of specificity for the target
* Easier to establish SAR
* Accelerates optimisation programme
* Dose size
* Near neighbours provides further confirmation that the hit is
not a spike and could be worth following-up
– LiPE is tracked in a lead optimisation programme to ensure potency trends
143
amine pKa equation
amine pKa in gas phase inductive dominate primary < secondary
144
half life and c max to c min ratio
Shorter t1/2 - greater peak:trough ratio and higher dose to maintain Cmin > efficacy
* Unless drug is very well-tolerated, once-a-day drug dosing usually requires a long half-
life (e.g. at least 12 hrs)
Long half-life driven by: Large volume of distribution Low clearance
