GOODMAN AND GILMAN'S THE
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 62-year-old patient with advanced osteoarthritis is enrolled in
a first-in-class small-molecule program targeting a newly
identified protease implicated in cartilage degradation. Lead
,optimization must balance potency with oral bioavailability.
Which chemical property modification during lead optimization
most directly increases passive intestinal permeability while
minimizing P-glycoprotein efflux liability?
A. Increase polar surface area (PSA) by adding hydroxyl groups.
B. Increase lipophilicity (logP) moderately while reducing
hydrogen bond donors.
C. Introduce a permanently charged quaternary ammonium
group.
D. Increase molecular weight by appending polar oligopeptide
tails.
Correct Answer
B
Rationale — Correct (B)
Moderately increasing lipophilicity and reducing hydrogen bond
donors lowers polarity and hydrogen bonding with aqueous
milieu, enhancing passive transcellular permeability. Reducing
H-bond donors also reduces recognition by efflux transporters
like P-gp, improving net absorptive flux. These changes often
improve oral bioavailability while maintaining potency if
metabolic liabilities are managed.
Rationale — Incorrect
A. Adding hydroxyls raises PSA and H-bonding — decreases
passive permeability and often increases efflux.
C. Quaternary ammonium creates permanent charge, severely
limiting passive membrane permeation.
,D. Increasing molecular weight with polar peptide-like additions
raises PSA and reduces passive absorption; also increases
metabolic instability.
Teaching Point
Moderate lipophilicity + fewer H-bond donors → better passive
gut permeability and less efflux.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Natural Products & Ethnopharmacology in Early Lead
Identification
Stem
A research group isolates a plant alkaloid showing nanomolar
inhibition of a cardiac sodium channel in vitro but demonstrates
rapid hepatic metabolism in human liver microsomes. For
translational development as an antiarrhythmic, which strategy
best preserves activity while improving metabolic stability?
A. Add a metabolically labile benzylic methyl adjacent to the
heterocycle.
B. Replace a metabolically vulnerable methoxy with a fluorine
at the same position.
C. Increase overall molecular flexibility by adding a flexible alkyl
, linker.
D. Convert the tertiary amine to an N-oxide to reduce hepatic
clearance.
Correct Answer
B
Rationale — Correct (B)
Replacing metabolically labile methoxy groups with fluorine
reduces oxidative metabolism at that site because C–F bonds
resist cytochrome P450 oxidation while often retaining similar
steric and electronic properties, improving metabolic stability
without drastic changes to potency.
Rationale — Incorrect
A. Adding a benzylic methyl typically increases susceptibility to
oxidative demethylation.
C. Increasing flexibility often raises clearance by improving
access to metabolic enzymes and reducing binding specificity.
D. Converting to an N-oxide may alter basicity and channel
binding; N-oxides can be metabolically reduced back and have
unpredictable clearance.
Teaching Point
Strategic fluorination blocks metabolic hotspots and can
increase metabolic stability while preserving activity.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
PHARMACOLOGICAL BASIS OF
THERAPEUTICS
14TH EDITION
• AUTHOR(S)LAURENCE BRUNTON;
BJORN KNOLLMANN
TEST BANK
1
Reference
Ch. 1 — Drug Discovery: From Medicinal Plants to Computer-
Aided Drug Design
Stem
A 62-year-old patient with advanced osteoarthritis is enrolled in
a first-in-class small-molecule program targeting a newly
identified protease implicated in cartilage degradation. Lead
,optimization must balance potency with oral bioavailability.
Which chemical property modification during lead optimization
most directly increases passive intestinal permeability while
minimizing P-glycoprotein efflux liability?
A. Increase polar surface area (PSA) by adding hydroxyl groups.
B. Increase lipophilicity (logP) moderately while reducing
hydrogen bond donors.
C. Introduce a permanently charged quaternary ammonium
group.
D. Increase molecular weight by appending polar oligopeptide
tails.
Correct Answer
B
Rationale — Correct (B)
Moderately increasing lipophilicity and reducing hydrogen bond
donors lowers polarity and hydrogen bonding with aqueous
milieu, enhancing passive transcellular permeability. Reducing
H-bond donors also reduces recognition by efflux transporters
like P-gp, improving net absorptive flux. These changes often
improve oral bioavailability while maintaining potency if
metabolic liabilities are managed.
Rationale — Incorrect
A. Adding hydroxyls raises PSA and H-bonding — decreases
passive permeability and often increases efflux.
C. Quaternary ammonium creates permanent charge, severely
limiting passive membrane permeation.
,D. Increasing molecular weight with polar peptide-like additions
raises PSA and reduces passive absorption; also increases
metabolic instability.
Teaching Point
Moderate lipophilicity + fewer H-bond donors → better passive
gut permeability and less efflux.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
2
Reference
Ch. 1 — Natural Products & Ethnopharmacology in Early Lead
Identification
Stem
A research group isolates a plant alkaloid showing nanomolar
inhibition of a cardiac sodium channel in vitro but demonstrates
rapid hepatic metabolism in human liver microsomes. For
translational development as an antiarrhythmic, which strategy
best preserves activity while improving metabolic stability?
A. Add a metabolically labile benzylic methyl adjacent to the
heterocycle.
B. Replace a metabolically vulnerable methoxy with a fluorine
at the same position.
C. Increase overall molecular flexibility by adding a flexible alkyl
, linker.
D. Convert the tertiary amine to an N-oxide to reduce hepatic
clearance.
Correct Answer
B
Rationale — Correct (B)
Replacing metabolically labile methoxy groups with fluorine
reduces oxidative metabolism at that site because C–F bonds
resist cytochrome P450 oxidation while often retaining similar
steric and electronic properties, improving metabolic stability
without drastic changes to potency.
Rationale — Incorrect
A. Adding a benzylic methyl typically increases susceptibility to
oxidative demethylation.
C. Increasing flexibility often raises clearance by improving
access to metabolic enzymes and reducing binding specificity.
D. Converting to an N-oxide may alter basicity and channel
binding; N-oxides can be metabolically reduced back and have
unpredictable clearance.
Teaching Point
Strategic fluorination blocks metabolic hotspots and can
increase metabolic stability while preserving activity.
Citation
Brunton, L. L., & Knollmann, B. C. (2023). Goodman & Gilman’s
The Pharmacological Basis of Therapeutics (14th ed.). Ch. 1.
