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ddd > Lead Optimization > Flashcards

Lead Optimization Flashcards

1
Q

__________________ was about activity
(pharmacodynamics), and therefore a sort of
“pharmacodynamic SAR”

A

Hit-to-lead generation

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2
Q

Lead optimization is where “_________ and ___________ SAR” is given emphasis for the first time.

A

pharmacokinetic and
toxicity SAR

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3
Q

Controlling polarity/lipophilicity is effective at _____________
(increasing/reducing) both toxicity and potential drug
interactions

A

reducing

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4
Q

requires a balance of hitting the “right”
spots and avoiding the “wrong” ones

A

Optimization

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5
Q

In Lead Optimization, focus is given to _____________________ like
being successfully absorbed or successfully binding
to the target

A

positive phenomena

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6
Q

their actions may be quite different from, or
even opposed to, those of the primary
target, leading to undesired effects

A

Related family
members

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7
Q

Assist in eliminating drugs from the
system. Inhibiting these off-targets can
result in drug-drug interactions.

A

Cytochrome
P450
enzymes

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8
Q

may be involved in
regulating the extent to which drugs are
concentrated inside vs outside of cells or
the extent to which drugs are absorbed
from the intestine. Inhibiting these
off-targets can result in drug-drug
interactions.

A

Transporters

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9
Q

Has a role in maintaining proper heart
rhythm; inhibition can lead to fatal
arrhythmias

A

hERG channel

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10
Q

(aka “antitargets”)

A

“off-targets”

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11
Q

T/F: there are “off-targets” (aka “antitargets”) where
negative results are more desired!

A

T

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12
Q

DRUGLIKENESS RULES

A

Veber rules, Ghose rules,
and most importantly Lipinski’s rules

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13
Q

According to Lipsinki’s Rule, of 5 logP value must not be ________ (more than/less than) 5

A

< 5

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14
Q

According to Lipsinki’s Rule, logP value of <5 indicates that it (has/does not have) polarity

A

has polarity

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15
Q

Required MW according to Lipsinki’s Rule

A

MW < 500 (must be small enough to fit target)

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16
Q

T/F: Some compounds with MW
greater than 500 can have druglike property.

A

T

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17
Q

HBD of fewer than 5 H-bond donors

A

HBD: Partially positive

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18
Q

Less than 10 H-bond acceptors

A

HBA: Partially negative

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19
Q

T/F: All HBA are HBD but not all HBD are HBA.

A

T

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19
Q

Drug metabolism and pharmacokinetics (DMPK)
studies are done in order to:

A

○ Ensure the drug is optimally delivered to its
intended site of action
○ Allow estimation of human PK and clinical dose
○ Minimize potential for reactive sites, toxicities,
and drug interactions

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19
Q

DMPK CONSIDERATIONS

A

-ABSORPTION AND BIOAVAILABILITY
-AVOIDANCE OF DRUG INTERACTIONS
-CLEARANCE OPTIMIZATION

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20
Q

can be used as early screen if
absorption or permeability is an issue in the existing
project

A

Caco-2 assay

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21
Q

an assay specific to human
colon epithelial cancer cell.

A

Caco-2 assay

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22
Q

It is essential to understand the enzymatic source of
the instability and to _________ (include/exclude) other clearance
mechanisms

A

exclude

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23
Q

Two main types of CYP inhibition assays

A

Fluorescence based assays
LCMS-based assay

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24
Q

best for initial
profiling of large numbers of compounds

A

Fluorescence based assays

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25
Q

more expensive and have
less throughput, but are more predictive

A

LCMS-based assay

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26
Q

a potential liability for reactive
metabolites

A

Risk for CYP inhibition

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27
Q

Risk of drug interaction based on _________________ is usually small and is rarely observed

A

phase 2 metabolism

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28
Q

Evaluation of _________ and __________ should be evaluated in early discovery

A

P-gp inhibition and plasma protein
binding

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29
Q

Identification of clearance mechanisms kinetic
studies in animals and human in vitro tools for
hepatic clearance

A

CLEARANCE OPTIMIZATION

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30
Q

Once a project has established means to predict
lipophilicity and pKa of the test compounds,
experiments measuring clearance can be conducted
using whole ______________ or (more commonly)
________________

A

hepatocytes; microsomes

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31
Q

In Silico Filters are (more/less) reliable than in vitro experiments,

A

less

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32
Q

can be used if after all H2L
stages, the current leads are still too many

A

virtual PK/DMPK

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33
Q

Commonly used In Silico Filter

A

SwissADME

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34
Q

can be
seen in SwissADME

A

Absorption and bioavailability, avoidance of drug
interactions, and overall druglikeness

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35
Q

T/F: It is impossible to make use of our PD and PK
SARs if we don’t know the considerations in
synthesizing new leads!

A

T

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36
Q

During _________, combinatorial or parallel synthesis are
sort of “mass-produced”,

A

H2L

37
Q

in _____________, we
“handcraft” few compounds

A

optimization

38
Q

Type of analogue that has both pharmacologic similarity and chemical similarity

A

Direct

39
Q

Type of analogue that doesn’t have pharmacologic similarity but has chemical similarity

A

Structural

40
Q

Type of analogue that has pharmacologic similarity but doesn’t have chemical similarity

A

Functional

41
Q

H2 blocker & proton pump
inhibitor

A

Functional analogues

42
Q

Analogue-based approaches has been criticized as
being mainly restricted to _________ compounds

A

me-too

43
Q

this is used to cancel out promiscuous, toxic, or bad ADME compounds

A

Predictive filters

44
Q

pairs or groups of structurally
similar or analogous compounds that are active
against the same target

A

Activity cliffs

45
Q

an opportunity to derive dissimilar
compounds (structural/functional analogues), with
patentability as goal

A

ANALOGUES in Drug Discovery

46
Q

Shifting to drastically different structure

A

(“scaffold hopping”)

47
Q

Shifting to drastically different structure (“scaffold hopping”) is dangerous if done blind, and highly flexible guides like __________ or ___________ can be utilized

A

pharmacophores or docking
set-ups

48
Q

If your strategy involves _________ (i.e. isosteres
or scaffold hopping), you must know the chemical properties behind the substituents you want to switch.

A

replacement

49
Q

Ligand equivalent that perform VdW

A

Hydrophobic groups

50
Q

Ligand equivalent that perform VdW, but often separate
from other hydrophobics because of
resonance (ex. Benzenes, heterocycles)

A

Aromatic groups

51
Q

Ligand equivalent that has “that” hydrogen

A

Hbond Donors (HBD) (Ex. OH, NH, COOH)

52
Q

O, N, S, or other
electronegative atoms (Ex. Br, O, F, I, N, C,
H)

A

Hbond Acceptors (HBA)

53
Q

STRATEGIES FOR ANALOGUE SYNTHESIS

A

SIMPLIFICATION
EXTENSION
RIGIDIFICATION OR GEOMETRY ALTERATION
REPLACEMENT

54
Q

SIMPLIFICATION strategies

A

A. Open chain contraction
B. Ring contraction
C. Ring deletion

55
Q

Once the essential groups of such a drug have been
identified, it is possible to discard the non-essential
parts of the structure without losing activity

A

SIMPLIFICATION

56
Q

EXTENSION strategies

A

A. Homologation (ex. 2C, 3C, and 4C lengths of the
same thing)
B. Substituent addition
C. Ring expansion
D. Ring addition

57
Q

Involves the addition of another functional group or
substituent to the lead compound

A

EXTENSION

58
Q

Allows one to probe the length, depth, or width of the
pocket

A

EXTENSION

59
Q

In Extension strategy, choosing a substituent that will fill the pocket will
then __________ (increase/decrease) the binding interaction

A

increase

60
Q

make sure that there is a definite and specific
interaction once the drug already attach to the drug
target

A

EXTENSION

61
Q

Whether or not the additional substituents have
significant impact will only be answered by __________

A

lab results

62
Q

Reduces possible conformations

A

RIGIDIFICATION OR GEOMETRY ALTERATION

63
Q

excessive flexibility = _________ (desirable/undesirable)

A

Undesirable

64
Q

too flexible molecules move too
much that they ___________ (stabilize/do not stabilize) their selves for
receptor binding

A

do not stabilize)

65
Q

too flexible molecules bind with
multiple targets, causing __________

A

side effects

66
Q

T/F: Some extension strategies don’t probe for space, but
are actually rigidifcations in disguise

A

T

67
Q

can cause steris effect enough to
“lock molecules” together, reduce their flexibility

A

Alkyl groups

68
Q

REPLACEMENT strategies

A

Isosteric replacement
Scaffold hopping

69
Q

replacement strategy that causes slight changes only

A

Isosteric replacement

70
Q

replacement strategy that causes extreme changes

A

Scaffold hopping

71
Q

replacement strategy for discovering a structurally novel compound

A

Scaffold hopping

72
Q

Sometimes, adding or replacing something in the
structure can make them ________(less/more) susceptible to
metabolism and premature deactivation

A

less

73
Q

Use of bioisosteres to increase absorption

A

REPLACEMENT

74
Q

SUBSTITUENT AND ISOSTERE CONSIDERATIONS

A

ALKENES AND ALKANES
ALCOHOLS AND PHENOLS
AMINES (PRIMARY AND SECONDARY)
AMIDES AND ESTERS

75
Q

Alkenes and Alkanes hydrocarbons are _________

A

nonpolar

76
Q

Alkenes and Alkanes can interact with hydrophobic parts (ex. phe, leu, ile,
trp) by ______________

A

Van der Waals forces

77
Q

may be done to “unfold the molecule”
may produce more steric effect

A

Saturation

78
Q

In ALCOHOLS AND PHENOLS, Oxygen as __________, hydrogen as __________

A

HBA; HBD

79
Q

Synthesizing an ___________ analogue removes the H →
abolish HBD power

A

ester

80
Q

HBD has no impact

A

Interaction persists

81
Q

Interaction stops

A

HBD is important

82
Q

In Amines, Nitrogen as ________, hydrogen as ______

A

HBA; HBD

83
Q

have N–H groups and can act as
HBD,

A

1o and 2o amines

84
Q

don’t have N–H groups, therefore can’t act as HBD

A

Tertiary amines

85
Q

Convert a 1o or 2o amine to 3o to ________ (abolish/establish) HBD
power

A

abolish

86
Q

In Amide and Esters, Carbonyl oxygen acts as ________

A

HBA

87
Q

Any N–H hydrogen of amides is a

A

HBD

88
Q

Conversion of Amides and Esters to _______ could be done to see if
carbonyl HBA is important

A

amine

89
Q

Conversion to ___________ would test the importance
of both HBA and HBD

A

alkenes

90
Q

are purely HBA (no HBD at all)

A

Esters

91
Q

Conversion of Esters to ____________ would test the importance
of HBA

A

alkenes

ddd (3 decks)

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