Pro-drugs and Soft-drugs

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Questions and Answers

What is the primary rationale behind employing soft-drug design in pharmaceutical development?

To mitigate potential side effects and toxicity by promoting rapid deactivation and limiting systemic exposure. (correct)
To enhance the drug's activity by forming multiple active metabolites with diverse biological activities.
To prolong the duration of action of the drug, ensuring sustained therapeutic effects.
To increase the drug's bioavailability across various routes of administration.

How does the metabolism of soft drugs differ fundamentally from that of prodrugs?

Soft drugs are deactivated by metabolism after exerting their effect, whereas prodrugs are activated by metabolism to become active. (correct)
Soft drugs undergo metabolism to form multiple active metabolites, while prodrugs are metabolized into a single active compound.
Soft drugs are activated by metabolism, whereas prodrugs are deactivated.
Soft drugs bypass metabolism entirely, whereas prodrugs require metabolism for their excretion.

What is a key chemical property that is often incorporated into soft drugs to facilitate their deactivation?

Incorporation of a functional group that promotes oxidation.
Resistance to enzymatic hydrolysis to maintain stability.
Introduction of a metabolically labile group that is susceptible to hydrolysis. (correct)
Stabilization against metabolic transformations to ensure prolonged activity.

If a traditional drug has a broad distribution and multiple active metabolites, what advantage does a soft drug analogue offer in terms of metabolic predictability?

A soft drug analogue undergoes controlled and predictable metabolism to inactive species, reducing the risk of varied biological activities from multiple metabolites. (C) Signup and view all the answers

Consider a scenario where a drug candidate shows excellent therapeutic efficacy but poses significant systemic toxicity due to its long half-life and widespread distribution. How could the soft drug approach be applied to mitigate these issues?

By designing a soft drug analogue that undergoes rapid metabolism to inactive metabolites, limiting its systemic exposure and reducing the duration of action. (C) Signup and view all the answers

Which strategy best describes the retrometabolic drug design approach for soft drugs?

Starting with an inactive metabolite and modifying it to introduce activity while incorporating a metabolically labile bond. (B) Signup and view all the answers

In the context of soft drug design, what is the primary purpose of incorporating a metabolically labile bond into a drug's structure?

To facilitate predictable and rapid metabolism of the drug into inactive metabolites, minimizing systemic exposure. (D) Signup and view all the answers

How does the soft drug approach, exemplified by soft beta-blockers, aim to improve upon traditional beta-blockers like Metoprolol?

By minimizing systemic exposure through rapid metabolism into inactive metabolites, potentially reducing off-target effects. (B) Signup and view all the answers

Considering the retrometabolic design of soft beta-blockers, what is the rationale behind creating esters of a major metabolite of Metoprolol?

Ester formation introduces a metabolically labile bond, potentially leading to rapid hydrolysis and inactivation. (D) Signup and view all the answers

What is a key difference between traditional drug design and retrometabolic soft drug design?

Traditional drug design starts with active compounds, while retrometabolic design starts with inactive metabolites. (B) Signup and view all the answers

Why is it crucial to avoid excessive modification of a known active molecule during drug design?

To maintain, rather than lose or alter, the molecule's intended pharmacological activity. (B) Signup and view all the answers

What is the primary consideration when introducing a metabolically sensitive group into a lead compound?

To minimize alterations to the lead compound's physical, steric, and electronic properties. (D) Signup and view all the answers

What is a metabolisable isostere in the context of drug design?

A functional group with similar electronic and steric properties that can be metabolized. (C) Signup and view all the answers

Which functional groups are most commonly employed as metabolically sensitive groups in drug design?

Esters, carbamates and quaternary nitrogens. (B) Signup and view all the answers

In the context of Remifentanil, what is the role of the ester group?

To serve as an isostere for a phenyl ring, facilitating rapid hydrolysis and short duration of action. (D) Signup and view all the answers

Considering the structures of Fentanyl, Carfentanil, and Remifentanil, what structural modification in Remifentanil contributes most significantly to its rapid metabolism and short duration of action, compared to the other two?

The replacement of a phenyl group with an ester group. (A) Signup and view all the answers

Why is Remifentanil considered a potent analgesic despite its structural similarities to Fentanyl and Carfentanil, given that the introduction of metabolically sensitive groups should not overly change the molecule's properties?

The ester group is an isostere of the phenyl ring, maintaining similar electronic and steric properties required for receptor interaction. (C) Signup and view all the answers

Based on the provided information, what is the primary mechanism by which modifications to the ester 'R' group influence the duration of action of a drug?

By influencing the rate of metabolic breakdown (hydrolysis) of the drug in the bloodstream, thus controlling its half-life. (B) Signup and view all the answers

Remifentanil exhibits rapid dissipation of analgesic effects post-infusion. What is the most likely explanation for this phenomenon, based on the information provided?

Remifentanil is rapidly metabolized by esterases in the blood, leading to a short half-life and quick termination of its effects. (A) Signup and view all the answers

How does increasing the carbon chain length of the ester 'R' group (from methyl to heptyl) affect the half-life of the analgesic in human blood, according to the table?

It significantly increases the half-life, implying slower metabolism. (D) Signup and view all the answers

Given that remifentanil is infused at a rate of 2 pg/kg per min, what is the implication of the finding that there is 'no evidence for accumulation of remifentanil.HCl during a 60-min infusion'?

The rate of remifentanil metabolism and elimination is equal to the infusion rate, preventing an increase in plasma concentration over time. (C) Signup and view all the answers

If a drug has a long context-sensitive half-time, what is the implication for its clinical use?

The drug's effects will persist longer after stopping the infusion, especially after prolonged use, potentially delaying recovery. (B) Signup and view all the answers

A researcher aims to design a novel analgesic with an ultra-short duration of action. Based on the principles illustrated by remifentanil, which structural modification would be most effective?

Incorporating an ester linkage readily hydrolyzed by plasma esterases to facilitate rapid drug inactivation. (B) Signup and view all the answers

How does the potency of the metabolite of remifentanil compare to that of remifentanil itself?

The metabolite has approximately 4600 times less potency than remifentanil. (A) Signup and view all the answers

If a patient exhibits unexpectedly prolonged respiratory depression following a remifentanil infusion, despite its known short half-life, what could be a plausible explanation, considering the provided data?

The patient also received a drug that inhibits plasma esterases, slowing down remifentanil metabolism. (C) Signup and view all the answers

Based on the information provided, if you wanted to create a drug with similar properties to remifentanil, but with a longer half-life, what alteration to the molecule might achieve this?

Use an ester 'R' group with more carbons. (B) Signup and view all the answers

Based on the data provided, if Alfentanil is a short acting analog of fentanyl, is it considered a 'soft drug'?

No, it is not considered a 'soft drug' because the context states explicitly it is 'not a soft-drug'. (B) Signup and view all the answers

Flashcards

Metabolism in Drug Design

Designing drugs to utilize metabolism for improvement.

Pro-drugs

Inactive compounds activated by metabolism to become active drugs.