med chem part 8

Question 1

differentiate and rationalize the difference in strengths between tacroliumus (0.03%) and pimecrolimus (0.1%)

Answer 1

tacrolimus is an ointment and therefore permeates better — lower strength

pimecrolimus is a cream

Question 2

which enters the skin more completely - an ointment or a cream

Answer 2

ointment - more occlusive

Question 3

which has greater lipophilicity and why - tacrolimus or pimecrolimus

Answer 3

tacrolimus: OH and allyl

pimecrolimus: Cl + ethyl

pimecrolimus is more lipophilic.
not only is chlorine more lipophilic than OH, but ethyl is much less polarizable than allyly

Question 4

explain the mechanism of calcineurin inhibition

Answer 4

normally, calcineurin catalyzes the dephosphorlyation of NFATp, which leads to the transcription of inflammatory cytokines in the nucleus

calcineurin inhibitors bind to the endogenous calcineurin inhibitor called CYCLOPHILIN which thus leads to suppressed T cell activation and cytokine transcription

Question 5

calcineurin is an enzyme dependent on what 2 things

Answer 5

calcium and calmodulin

Question 6

what is the only topical PDE4 (phosphodiesterase 4) inhibitor

Answer 6

crisaborole (eucrisa)

Question 7

in the structure of crisaborole, what is NECESSARY to be at the 5 position

what is necessary to be at 4? any substitutions?

Answer 7

the aryloxyl moeity

cyano (CN) must be at 4 prime, but it can be replaced with CF3, morpholine moeity

Question 8

as mentioned, the CN at position 4 on crisaborole can be replaced by trifluromethyl (CF3) and a morpholine moeity

what can it NOT be replaced by

Answer 8

Sulfonamide!!
activity will be lost

Question 9

explain what PDE4 does normally in AD patients, without an inhibitor like crisaborole

Answer 9

ATP produces cAMP.

cAMP is hydrolyzed to 5’-AMP through PDE4

PDE4 levels are elevated in people with AD. therefore, there will be decreased amounts of cAMP since it is all being converted to 5’-AMP through the excess levels of PDE-4

this decreased cAMP leads to production of inflammatory cytokined

Question 10

how does crisaborole treat AD

Answer 10

blocks PDE4, thus increasing cAMP levels and decreasing the amount of cytokines produced

T cell activity is suppressed

Question 11

true or false

high cAMP levels = not a lot of cytokines produced

Answer 11

true

Question 12

MOA of dupilumab (dupixent)

Answer 12

monoclonal antibody

targets IL-4a subunit which is on BOTH IL-4 and IL-13 receptors

therefore, blocks IL-4 and IL-13 cytokines from binding to their receptors and initiating inflammation

Question 13

what happens when IL-4 and IL-13 bind to their receptors?

Answer 13

switch Th0 to Th2 cells – leading to inflammation in AD

Th2 cells further the production of IL-4 and IL-13
so preventing this switch prevents inflammation in multiple ways

Question 14

true or false

dupilumab helps to reduce inflammation

Answer 14

true!!!
blocks IL-4a subunit on IL-4 and IL-13 receptors – prevents cytokines from binding and invoking inflammatory response

Question 15

besides helping reduce inflammation, name 2 other effects of dupilumab

Answer 15

improves skin barrier
breaks itch-scratch cycle

Question 16

dupilumab is indicated for what patients

Answer 16

age 6 and older with moderate to severe AD

Question 17

______ is an ORAL JAK1 selective inhibitor

Answer 17

Abrocitinib

Question 18

what is common and necessary to ALL kinase inhibitors

Answer 18

2 hydrogen bonds needed with HINGE REGION —- need H bond acceptor (sp2) and h bond donor (sp3) on drug candidate

Question 19

besides abrocitinib, name 2 other JAK inhibitors for AD

Answer 19

baricitinib
upadacitinib

Question 20

why is it hard to develop a selective kinase (like JAK) inhibitor?

Answer 20

because the hinge region has a common requirement - 2 H bonds

Question 21

Abrocitinib is indicated for….

Answer 21

moderate to severe AD

Question 22

name 3 important structural aspects of Abrocitinib

Answer 22

-1,3 CIS cyclobutyl is necessary for JAK1/JAK2 selectivity. cannot be trans

-the alkyl group on sulfonamide must be SMALL to give potency, selectivity, and metabolic stability

pyrroleopyrimidine gives hinge region binder (HINGE = COMMON TO ALL JAKS)

Question 23

• which cytokines are involved in ACUTE atopic dermatitis

Answer 23

IL4
IL13

Question 24

*which cytokines are involved in CHRONIC atopic dermatitis

Answer 24

IL4
IL13
IL22

Question 25

explain how helper T cells are involved in AD

Answer 25

when resident dendritic cells are activated, they migrate to local lymph nodes. there, they polarize naive T cells to Th2.

Th2 cells induce isotype switching in B cells.
leads to elevated IgE levels

Th2 cells recruited BACK to the skin and induce skin inflammation by cytokines (accompanied by Th22)

Question 26

differentiate between the T cells involved in acute vs chronic AD

Answer 26

acute - Th2, Th22

chronic - Th1, Th2, T22