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Medicinal Chemistry > MED CHEM > Flashcards

MED CHEM Flashcards

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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

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2
Q

oral bioavailability

A

measure of degree to which a drug reaches systemic circulation following oral dosing F%

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3
Q

equation for oral bioavailiabilty

A

AUCoral/AUCiv x Doseiv/Doseoral x 100

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4
Q

relationship between half life volume and clearance in minutes

A

T1/2 = 0.693 x Vd(mL/Kg)/Cl(mL/min/Kg)

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5
Q
A
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6
Q

relationship between half life volume and clearance in hours

A

T1/2 = 12 x Vd(L/Kg)/Cl(mL/min/Kg)

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7
Q

What is Clearance

A

volume of blood cleared of drug per unit time want low

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8
Q

liver blood flow rate

A

20ml/min/kg

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9
Q

Kidney blood flow rate

A

2ml/min/kg

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10
Q

How to tell if clearance is renal or hepatic

A

renal logD7.4<0 hepatic logD7.4>0

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11
Q

Pharmacodynamics

A

study of pharmacological response to a drug, potency, selectivity what the drug does to the body

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12
Q

Pharamcokinetics

A

movement of a drug through the body
ADME simply: what the body does to the drug

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13
Q

lipophlic log P

A

postive

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14
Q

polar log P

A

negative

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15
Q

log P Me

A

0.5

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16
Q

Et

A

1

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17
Q

Cl

A

0.7

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18
Q

CF3

A

0.9

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19
Q

pH

A

1.9

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20
Q

F

A

0.15

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21
Q

H

A

0

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22
Q

CN

A

-0.5

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23
Q

CONH2

A

-1.4

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24
Q

SO2NH2

A

-1.8

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25
Q

SO2Me

A

-1.6

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26
Q

What is Ligand efficiency

A

free binding energy per heavy atom measure how well compound binds relative to size (Kcalmol^-1/heavy atom)

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27
Q

equation for ligand efficiency

A

-RTlnKi/HAC -1.4log(IC50)/HAC <0.2 = poor 0.3 = satisfactory >0.4 high

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28
Q

polarity

A

measure of how hydrophilic a compound is

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29
Q

polar compound selectivity

A

good

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30
Q

polar compound solubility

A

good

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31
Q

polar compound safety

A

good

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32
Q

polar compounds stability

A

good metabolic stability

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33
Q

polar compound half life

A

short

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34
Q

polar compound absorption

A

poor transcellular absorption from gut

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35
Q

polar compound VoD

A

short

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36
Q

ionisation

A

measure of degree to which compound charged under physiological conditions

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37
Q

solubility in gut for positively charged

A

good solubility in gut slightly acidic

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38
Q

positively charged VoD

A

high volume of distribution

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39
Q

positive absorption

A

reduced absorption

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40
Q

positive charged safety

A

ion channel based safety issues

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41
Q

negative charged compound solubility

A

improved solubility

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42
Q

negative charged compound

A

low VoD

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43
Q

negative charged compound absorption

A

reduced absorption

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44
Q

negative charged compound safety

A

good safety

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45
Q

negative charged compound selectivity

A

good selectivity

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46
Q

Drug Binding

A

Drug + protein <-> drug protein complex (Keq)

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47
Q

Drug dissociation

A

Drug Protein complex <-> Drug + Protein (Ki or Kd) ( greater affinity of drug for protein smaller KI)

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48
Q

IC50

A

concentration of drug required to inhibit the protein of block binding to the protein by 50%

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49
Q

Hit

A

compound confirmed activity 5-0.5 microMolar against larger get protein activity with structurally relevant compounds may be confirmed

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50
Q

Candidate

A

single compound from lead series meets all minimum requirements for progress towards development

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51
Q

Lead

A

compound with potential to progress full drug

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52
Q

LogP

A

log( [Drug]octanol/[non ionised drug]water)

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53
Q

Log D

A

Log D (usually measure at ph7.4) = log ([drug]octanol/[ionised and non ionised drug]water)

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54
Q

What is lipophilicity

A

measure of how greasy a compound is

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55
Q

examples of lipophilic compounds

A

aliphatic chains aromatics halogen

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56
Q

Lipophilic compound selectivity

A

poor selectivity

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57
Q

lipophilic compound solubility

A

poor solubility

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58
Q

lipophilic compound stability

A

rapid removal metabolic instability

59
Q

What do you need lipophilicity for

A

transcellular absorption from gut VoD efficacy half life

60
Q

ligand lipophilicity efficiency

A

LiPE = - log(IC50) - clogP

61
Q

What is lipophilicity efficiency

A

measure of degree to which potency is driven by factors other than lipophilicity

62
Q

Base fraction unionised

A

1/(1+10^(pKa-pH))

63
Q

base fraction ionised

A

1/(1+10^(pH-pKa))

64
Q

Henderson Hasselbalch equation bases

A

pH = pKa + log10([B]/[BH+])

65
Q

acid fraction unionised

A

1/(1+10^(pH-pKa))

66
Q

acid fraction ionised

A

1/(1+10^(pKa-pH))

67
Q

Henderson Hasselbalch acid

A

pH= pKa+ log10([A-]/[HA])

68
Q

pKa + pKb

A

14

69
Q

Kb x Ka

A

Kw

70
Q

neutral compounds log P and D

A

log P = log D

71
Q

log D and fraction

A

log D = log P + log ( fraction unionised)

72
Q

Acids if pH-pKa>1

A

log D acids = logP +pKa -pH

73
Q

Bases if pKa – pH>1

A

log D bases = logP -pKa +pH

74
Q

Acid dissociation rule

A

pH<pKa -2 acid <1% dissociated <1% ionised
pH = pKa-1 acid approx. 10% dissociated approx. 10% ionised
pH = pKa acid approx. 50 % dissociated approx. 50% ionised
pH = pKa+1 acid approx. 90% dissociated approx. 90% ionised
pH>pKa +2 acid approx. 99% dissociated >99% ionised

75
Q

Base dissociation rule

A

pH<pKa -2 BH+ <1% dissociated >99% 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
Q

Volume of Distribution

A

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
Q

bases

A

molecule which can gain proton from water

78
Q

zwitterion

A

molecule with acidic and basic functional group

79
Q

acid

A

molecule which can lose a proton to water

80
Q

How to maximise oral bioavailability

A

minimise dose cost waste toxicity risk interpatient variability

81
Q

drug 1/2 life

A

time taken for drug plasma conentration to reduce by 50%

82
Q

more lipophilic

A

more toxicity

83
Q

less lipophilic

A

less toxicity

84
Q

Ka acid

A

[H3O+][A-]/ [HA] = 55.5Keq

85
Q

Kb basic

A

[BH+][OH-]/[B] = 55.5Keq

86
Q

less ionised compounds

A

closer log P and log D are

87
Q

neutral compound examples

A

carboxamides heteroatomics sulphonamides ketones ethers alcohol

88
Q

Phase 2 metabolism

A

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
Q

Phase 1 metabolism

A
  • 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
Q

block metabolism by

A

adding fluorine to get rid of metabolic susceptibility of C-H

91
Q

VoD and lipophilicity

A

VoD increases with increasing lipophilicity

92
Q

acidic VoD

A

0.2 -2 L/Kg majority of drug withing total body of water cellular penetration limited

93
Q

Basic VoD

A

0.5-30 favourable interaction between positive charge on drug and negatively charge phospholipid bilayer of cellular membrane

94
Q

Absorption

A

– process whereby drug moves from site of administration into the body
– for oral drugs, this means crossing the gastro-intestinal tract

95
Q

Distribution

A

– reversible transfer of drug from site of measurement (i.e. blood / plasma) into
other tissues

96
Q

Metabolism

A

– process by which the body modifies drugs to make them more easily excreted

97
Q

Excretion

A

– irreversible transfer of drug from site of measurement (e.g. blood / plasma)
– majority of excretion usually occurs via the urine or faeces

98
Q

log P

A

measure of lipophilicity under non ionised condtions

99
Q

logD

A

measure of lipophilicity under physiological conditions

100
Q

log D same as log P

A

as long as pKa not change

101
Q

predicting log P

A

The fragment logP values are used collectively in algorithms giving clogP Unusual’ functional groups poorly parameterised and clogP may be misleading.

102
Q

Drug discovery process

A

Disease and pathway -> target selection -> hit identification -> hit to lead -> lead optimisation ( identify clinical candidate) -> scale up clinical trials

103
Q

How and when compounds die

A

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
Q

How long does it take to get a drug to market

A

10-15 years

105
Q

How much does it cost to get a drug to market

A

1-2 billion

106
Q

How many compounds does it take to get 1 drug to market

A

20-30 years

107
Q

what type of druggable targets are there

A

kinases GPCRs and ion channels

108
Q

hERG potassium ion channels

A

blocks to prolong QT causing Sudden Death (Torsade dePoints)

109
Q

CYP450s

A

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
Q

CYP450 reaction

A

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
Q

How do we select targets

A
  • 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
Q

gibbs binding

A
  • ΔGbinding = -RT ln (Keq) = RT ln (Ki)
113
Q

base graph

A

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
Q

acid graph

A

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
Q

target validation

A
  • 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
Q

Drug development process

A

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
Q

CYPs interact stronger

A

more lipophilic substrates

118
Q

log D and clearance

A

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
Q

druggable and less druggable compounds

A

Good surface contact achievable only with relatively large molecule = “less drugable”
Good surface contact achieved with a relatively compact molecule = “Drugable”

120
Q

acidic e- donating and withdrawing

A

e- donating reduce acidity (destabilise resultant negative charge after deprotonation)
e- withdrawing increase acidity ( stabilise resultant negative after deprotonation)

121
Q

basic group donating and withdrawing

A

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
Q

Target/mechanism types opportunities and issues

A
  • 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
Q

safety issues

A

cardiac ion channels with lipophilic bases safety issues anilines and nitro have higher toxicology risks

124
Q

How to find hit to lead compounds

A

– 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
Q

For neutral compounds

A

log D = log P

126
Q

for more ionised compounds

A

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
Q

D

A

distribution coefficient

128
Q

P

A

partition coefficient

129
Q

pKa of amino pyridines

A

5-9

130
Q

pKa of aliphatic amines

A

7-11

131
Q

pKa of phenol

A

9-10

132
Q

pKa of carboxylic acids

A

3-5

133
Q

oral bioavailability and clearance

A

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
Q

size and structural complexity

A
  • 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
Q

compounds that drive potency through polar interactions

A

high values of LiPE

136
Q

nM potency

A

LiPE 5-7

137
Q

compartment model

A

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
Q

more polar excreted product

A

renal excretion urine

139
Q

less polar excreted compound

A

biliary excretion faeces

140
Q

poly pharmacology

A

lack of selectivity for other targets lead optimisation much more challenging multiple SARs complicates biological profiling

141
Q

Drug absorption

A
  • 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
Q

Potency and ligand efficiency

A
  • 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
Q

amine pKa equation

A

amine pKa in gas phase inductive dominate primary < secondary <tertiary
aqueous phase solvation by water molecules solvate positive charge more N-H stronger solvation stabilisation opposing proton affinity of basic centre no substitutions < tri sub <mono sub=duo sub

144
Q

half life and c max to c min ratio

A

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

Medicinal Chemistry (1 decks)

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