6.8 MedChem of Antiemetics

Activates neurokinin 1 (NK1 ) receptors

Substance P (SP)

______ is a critical drug target for antiemetic therapy

5-HT3

Weak, non-selective 5-HT3 antagonist

Which are the structural Features Shared Among "Setrons"?

1) A bulky basic amino group

2) A carbonyl containing functional group (ketone, amide, or ester)

3) An aromatic/heteroaromatic ring

Ondansetron (molecule)

Granisetron (molecule)

Dolasetron (molecule)

Palonosetron (molecule)

"setrons" competitively bind to _______ binding site, they bind through ______ interaction between _________ and __________.

5-HT3

cation-π

typ156 and the positively charged amino group

The amino groups in setrons need to be ________ under physiological pH 7.4

basic enough so that can be protonated

B>C>A

A>C>B

(A most basic with highest pKa)

pKa is observed, because for the amine group to be protonated it needs to be highly protonized (+ charge). This happens at a pKa _________

higher than 7.5

(body pH is 7.5, so at a pKa of 7.5 aprox. 50% of drug is ionized. Higher pKa= higher percent of drug ionized)

Dolasetron is a ______ that is well absorbed (GI tract), and undergoes rapid first-pass metabolism

prodrug

Dolasetron is turned in the liver to the active metabolite ________ by the enzyme _________

Hydrodolasetron

Carbonyl reductase

Ondasetron has a ______ half-life due to ______

short (4 hrs)

due to positions at benzene that are easily oxidized by CYP enzymes -> rapid excretion

Palonosetron has a _______ half-life due to ____

long half-life

substitution (addition of ring) on positions that were easily oxidized by CYP enzymes

B. Ondasetron

1. Carbonyl reductase

2. Activation

Chemotherapy causes the release of _______ in chemoreceptor trigger zone (CTZ). ____ binds to and activates NK1 receptor in the vomiting center -> NKI receptor antagonists as antiemetics

substance P (SP), a 11- amino acid peptide

SP

In addition, inhibition of NK1 for CINV is mainly a CNS event, ________ may not be able to penetrate BBB

peptide antagonists

Benzhydryl group, caused undesirable interaction with Ca(II) channel

Increase stability by preventing oxidative metabolism

1. Addition of O to ring

2. Lower benzyl/phenyl (circled): still fills a hydrophobic pocket (potency), but remains metabolically vulnerable to debenzylation and ring oxidation

Decreased Ca(II) channel activity & improved bioavailability

Aprepitant (half-life 9-14 hrs)

Netupitant-> structural modifications from aprepitant increased half-life to 96 h

Rolapitant (elimination half-life around 7 days, which makes it good for delayed CINV)

_______ is a NK1 antagonist that has good oral bioavailability, low water solubility and requires a special formulation

Aprepitant

Adding a __________ to aprepitant molecule you create the prodrug ________, which is water soluble and has high efficacy for CINV.

phosphate group

Fosaprepitant

Fosaprepitant

Adding a __________ to Netupitant molecule you create the prodrug ________, which is water soluble.

Phosphate group

Fosnetupitant

(Fosnetupitant + Palonosetron (IV) combo approved by FDA for CINV)

Fosnetupitant

FG: Benzamide

Which are the D2 antagonists?

1. Metoclopramide (Benzamides)

2. Prochlorperazine (Phenothiazines)

FG: Phenothiazine

Prochlorperazine

_____ is an antipsychotic agent that belongs to phenothiazine class of antipsychotic agents. Its beneficial antiemetic "side effect" is through inhibiting D2 receptors

Prochlorperazine

FG: Benzodiazepines

Which antiemetics are good for ANTICIPATORY VOMITING?

Benzodiazepines: Lorazepam and Olanzapine

Benzodiazepines have an antiemetic mechanism due to a combination of ____, ________, and ______ of the vomiting center by blocking the effects of __________

- sedation, reduction in anxiety, and depression

- DA and 5-H

Olanzapine

Lorazepam

Dexamethasone

_________ are _______of the glucocorticoid receptor (GR)

Corticosteroids are agonists

For Corticosteroids the mechanism of antiemetic activity is unclear. They have______, which are believed to account for their antiemetic effect

anti-inflammatory activities

Corticosteroids are typically used in combination with a _______ or as a ___________

- 5-HT3 antagonist or

- third agent in combination with 5-HT3 and NK1 antagonists (depending on course of treatment)

THC (Dronabinol)

Nabilone (Cesamet)

For cannabinoids, the precise antiemetic mechanism unknown. Probably act by ______ of cannabinoid receptor around vomiting center and inhibiting neurotransmission

activating CB1 subtype

Cannabinoids are ______, which is important for penetrating the blood-brain barrier.

highly lipophilic compounds

Aprepitant (B), the other two were hit molecules that never became drugs. Methyl and F occupy the spaces that would make the drug susceptible.

C -> Dexamethasone

Which functional groups are different between cortisol and Dexamethasone?

Dexamethasone has:

- A double bond between C2-C1

- F on C9

- CH3 on C16

A. Phenothiazine (Prochlorperazine)

B. Benzamide (Metoclopramide)

C. Benzodiazepine (Olanzapine)

B

5-HT3 antagonists are?

-setrons

NK1 antagonists

-pitant