med chem part 8 Flashcards
differentiate and rationalize the difference in strengths between tacroliumus (0.03%) and pimecrolimus (0.1%)
tacrolimus is an ointment and therefore permeates better — lower strength
pimecrolimus is a cream
which enters the skin more completely - an ointment or a cream
ointment - more occlusive
which has greater lipophilicity and why - tacrolimus or pimecrolimus
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
explain the mechanism of calcineurin inhibition
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
calcineurin is an enzyme dependent on what 2 things
calcium and calmodulin
what is the only topical PDE4 (phosphodiesterase 4) inhibitor
crisaborole (eucrisa)
in the structure of crisaborole, what is NECESSARY to be at the 5 position
what is necessary to be at 4? any substitutions?
the aryloxyl moeity
cyano (CN) must be at 4 prime, but it can be replaced with CF3, morpholine moeity
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
Sulfonamide!!
activity will be lost
explain what PDE4 does normally in AD patients, without an inhibitor like crisaborole
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
how does crisaborole treat AD
blocks PDE4, thus increasing cAMP levels and decreasing the amount of cytokines produced
T cell activity is suppressed
true or false
high cAMP levels = not a lot of cytokines produced
true
MOA of dupilumab (dupixent)
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
what happens when IL-4 and IL-13 bind to their receptors?
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
true or false
dupilumab helps to reduce inflammation
true!!!
blocks IL-4a subunit on IL-4 and IL-13 receptors – prevents cytokines from binding and invoking inflammatory response
besides helping reduce inflammation, name 2 other effects of dupilumab
improves skin barrier
breaks itch-scratch cycle
dupilumab is indicated for what patients
age 6 and older with moderate to severe AD
______ is an ORAL JAK1 selective inhibitor
Abrocitinib
what is common and necessary to ALL kinase inhibitors
2 hydrogen bonds needed with HINGE REGION —- need H bond acceptor (sp2) and h bond donor (sp3) on drug candidate
besides abrocitinib, name 2 other JAK inhibitors for AD
baricitinib
upadacitinib
why is it hard to develop a selective kinase (like JAK) inhibitor?
because the hinge region has a common requirement - 2 H bonds
Abrocitinib is indicated for….
moderate to severe AD
name 3 important structural aspects of Abrocitinib
-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)
- which cytokines are involved in ACUTE atopic dermatitis
IL4
IL13
*which cytokines are involved in CHRONIC atopic dermatitis
IL4
IL13
IL22
explain how helper T cells are involved in AD
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)
differentiate between the T cells involved in acute vs chronic AD
acute - Th2, Th22
chronic - Th1, Th2, T22
