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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
Two main types of CYP inhibition assays
Fluorescence based assays LCMS-based assay
24
best for initial profiling of large numbers of compounds
Fluorescence based assays
25
more expensive and have less throughput, but are more predictive
LCMS-based assay
26
a potential liability for reactive metabolites
Risk for CYP inhibition
27
Risk of drug interaction based on _________________ is usually small and is rarely observed
phase 2 metabolism
28
Evaluation of _________ and __________ should be evaluated in early discovery
P-gp inhibition and plasma protein binding
29
Identification of clearance mechanisms kinetic studies in animals and human in vitro tools for hepatic clearance
CLEARANCE OPTIMIZATION
30
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) ________________
hepatocytes; microsomes
31
In Silico Filters are (more/less) reliable than in vitro experiments,
less
32
can be used if after all H2L stages, the current leads are still too many
virtual PK/DMPK
33
Commonly used In Silico Filter
SwissADME
34
can be seen in SwissADME
Absorption and bioavailability, avoidance of drug interactions, and overall druglikeness
35
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!
T
36
During _________, combinatorial or parallel synthesis are sort of “mass-produced”,
H2L
37
in _____________, we “handcraft” few compounds
optimization
38
Type of analogue that has both pharmacologic similarity and chemical similarity
Direct
39
Type of analogue that doesn't have pharmacologic similarity but has chemical similarity
Structural
40
Type of analogue that has pharmacologic similarity but doesn't have chemical similarity
Functional
41
H2 blocker & proton pump inhibitor
Functional analogues
42
Analogue-based approaches has been criticized as being mainly restricted to _________ compounds
me-too
43
this is used to cancel out promiscuous, toxic, or bad ADME compounds
Predictive filters
44
pairs or groups of structurally similar or analogous compounds that are active against the same target
Activity cliffs
45
an opportunity to derive dissimilar compounds (structural/functional analogues), with patentability as goal
ANALOGUES in Drug Discovery
46
Shifting to drastically different structure
(“scaffold hopping”)
47
Shifting to drastically different structure (“scaffold hopping”) is dangerous if done blind, and highly flexible guides like __________ or ___________ can be utilized
pharmacophores or docking set-ups
48
If your strategy involves _________ (i.e. isosteres or scaffold hopping), you must know the chemical properties behind the substituents you want to switch.
replacement
49
Ligand equivalent that perform VdW
Hydrophobic groups
50
Ligand equivalent that perform VdW, but often separate from other hydrophobics because of resonance (ex. Benzenes, heterocycles)
Aromatic groups
51
Ligand equivalent that has “that” hydrogen
Hbond Donors (HBD) (Ex. OH, NH, COOH)
52
O, N, S, or other electronegative atoms (Ex. Br, O, F, I, N, C, H)
Hbond Acceptors (HBA)
53
STRATEGIES FOR ANALOGUE SYNTHESIS
SIMPLIFICATION EXTENSION RIGIDIFICATION OR GEOMETRY ALTERATION REPLACEMENT
54
SIMPLIFICATION strategies
A. Open chain contraction B. Ring contraction C. Ring deletion
55
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
SIMPLIFICATION
56
EXTENSION strategies
A. Homologation (ex. 2C, 3C, and 4C lengths of the same thing) B. Substituent addition C. Ring expansion D. Ring addition
57
Involves the addition of another functional group or substituent to the lead compound
EXTENSION
58
Allows one to probe the length, depth, or width of the pocket
EXTENSION
59
In Extension strategy, choosing a substituent that will fill the pocket will then __________ (increase/decrease) the binding interaction
increase
60
make sure that there is a definite and specific interaction once the drug already attach to the drug target
EXTENSION
61
Whether or not the additional substituents have significant impact will only be answered by __________
lab results
62
Reduces possible conformations
RIGIDIFICATION OR GEOMETRY ALTERATION
63
excessive flexibility = _________ (desirable/undesirable)
Undesirable
64
too flexible molecules move too much that they ___________ (stabilize/do not stabilize) their selves for receptor binding
do not stabilize)
65
too flexible molecules bind with multiple targets, causing __________
side effects
66
T/F: Some extension strategies don’t probe for space, but are actually rigidifcations in disguise
T
67
can cause steris effect enough to “lock molecules” together, reduce their flexibility
Alkyl groups
68
REPLACEMENT strategies
Isosteric replacement Scaffold hopping
69
replacement strategy that causes slight changes only
Isosteric replacement
70
replacement strategy that causes extreme changes
Scaffold hopping
71
replacement strategy for discovering a structurally novel compound
Scaffold hopping
72
Sometimes, adding or replacing something in the structure can make them ________(less/more) susceptible to metabolism and premature deactivation
less
73
Use of bioisosteres to increase absorption
REPLACEMENT
74
SUBSTITUENT AND ISOSTERE CONSIDERATIONS
ALKENES AND ALKANES ALCOHOLS AND PHENOLS AMINES (PRIMARY AND SECONDARY) AMIDES AND ESTERS
75
Alkenes and Alkanes hydrocarbons are _________
nonpolar
76
Alkenes and Alkanes can interact with hydrophobic parts (ex. phe, leu, ile, trp) by ______________
Van der Waals forces
77
may be done to “unfold the molecule” may produce more steric effect
Saturation
78
In ALCOHOLS AND PHENOLS, Oxygen as __________, hydrogen as __________
HBA; HBD
79
Synthesizing an ___________ analogue removes the H → abolish HBD power
ester
80
HBD has no impact
Interaction persists
81
Interaction stops
HBD is important
82
In Amines, Nitrogen as ________, hydrogen as ______
HBA; HBD
83
have N–H groups and can act as HBD,
1o and 2o amines
84
don’t have N–H groups, therefore can't act as HBD
Tertiary amines
85
Convert a 1o or 2o amine to 3o to ________ (abolish/establish) HBD power
abolish
86
In Amide and Esters, Carbonyl oxygen acts as ________
HBA
87
Any N–H hydrogen of amides is a
HBD
88
Conversion of Amides and Esters to _______ could be done to see if carbonyl HBA is important
amine
89
Conversion to ___________ would test the importance of both HBA and HBD
alkenes
90
are purely HBA (no HBD at all)
Esters
91
Conversion of Esters to ____________ would test the importance of HBA
alkenes

ddd (3 decks)

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