Med Chem - Psoriasis Part 1 Flashcards
name the areas most commonly affected by psoriasis
knees, elbows, and scalp
psoriasis is a ____ ___ skin disorder leading to….
chronic inflammatory
leading to erythema, scaling, and thickening of the skin
as mentioned, psoriasis is a chronic inflammatory disease leading to erythema, scaling, and thickening of the skin
what causes this thickening
because of the hyperproliferation and abnormal differentiation of keratinocytes and the excessive amount of T cells coming to the surface (epidermis)
what is the cause of inflammation in psoriasis
cytokines
name 4 types of SYSTEMIC therapies for psoriasis
methotrexate
oral retinoids
PDE4 inhibitor
biologics
name 7 types of topical/external therapies for psoriasis
corticosteroids
calcineurin inhibitors
photo(chemo)therapy
AhR (aryl hydrocarbon) agonsit
calcipotriene
vitamin A analogs
anthralin
name a Vitamin A analog used in psoriasis
tazarotene
name an AhR (aryl hydrocarbon) agonist used in psoriasis
Tapinarof
what is PUVA
oral Psoralen + UVA
phototherapy used in psoriasis
what class is tacrolimus
calcineurin inhibitor - can be used in psoriasis
name 2 oral retinoids that can be used as systemic agents in psoriasis
etretinate
isotretinoin
name 4 biologics that can be used as systemic agents in psoriasis
alefacept
efalizumab
ustekinumab
ixekizumab
calcipotriene is a derivative of what? what is the brand name?
is it synthetic/natural/semisynthetic?
SYNTHETIC derivative of vitamin D3 (calcitriol)
Dovonex cream
calcipotriene is indicated for what kind of psoriasis
moderate plaque psoriasis
name 2 benefits of using calcipotriene cream (dovenox) over topical corticosteroids
1 .does not cause tachyphylaxis (when using for long periods of time, efficacy is reduced and need higher and higher strength) – not the case for calcipotriene
- less is absorbed systemically compared to steroids
which is more systemic absorption and why – topical corticosteroids or calcipotriene
steroids are absorbed more systemically
this is bc calcipotriene has more polar functional groups
differentiate between the structure of corticosteroids vs calcipotriene
in calcipotriene, the B ring of the steroid is OPENED through C9-C10 cleavage and is now an open chain
also, calcipotriene has more polar functional groups and is thus less systemically absorbed
another name for vitamin D3
calcitriol
what receptors does calcipotriene bind to?
what KIND of receptors are they?
vitamin D3 receptors
they are nuclear receptors – located inside of the cell
the vitamin D3 receptor belongs to the _______ receptor superfamily
steroid/thyroid receptor superfamily
it is a NUCELAR RECEPTOR
in what tissues/cells is the vitamin D3 receptor located?
what does this say about its efficacy in psoriasis if we target it?
vitamin D3 receptor is found inside the cells of many different tissues — including T cells – which are known to play a role in psoriasis!!!
the receptors are widely distributed in tissues all over the body inc in T cells - good target for psoriasis
explain the mechanism of action of calcipotriene
what endogenous molecule does it mimic?
mimics vitamin D3
binds to the vitamin D receptor (VDR) which forms a heterodimer with an RXR (retinoic acid receptor)
this transcriptional complex then goes to the nucleus where it modulates gene transcription by binding a palindromic sequence on DNA
what kind of dimer does VDR form when bound to calipotriene/vitamin D3?
heterodimer with RXR is preferred, but an alternate dimer is a homodimer with another VDR
heterodimer is more effective
name 3 different things that calcipotriene inhibits through binding to the DNA sequence and modulating transcription
inhibits:
-expression of proinflam. cytokines
-cell differentiation and proliferation of keratinocytes
-T cell proliferation
name 1 thing that calcipotriene actually INDUCES (not inhibits)
Tregs – they are responsible for SUPPRESSING the immune system and preventing an autoimmune response
what does ATRA stand for
all trans retinoic acid
is ATRA a flexible molecule?
why or why not?
YES - it is flexible
this is because of the alternating double bonds – allows the single bonds to rotate and cause the double bonds to isomerize to cis conformations
therefore, there are a wide range of ATRA conformation
All trans retinoic acid is the active form of what?
vitamin A
true or false
retinoic acids, in general , bind ALL RAR’s with no selectivity
true
differentiate between the structure of tazarotene and ATRA and what this means about its activity
tazarotene is RIDGID unlike ATRA
this is due to the carbon carbon triple bond in the middle of the molecule
this rigidity gives tazarotene greater selectivity — selective for RARB and RARY
true or false
tazarotene is a synthetic retinoid
true
acetylenic
refers to the carbon triple bond in tazarotene that makes it rigid and non-isomerizable
explain the SAR of tazarotene
it is a PRODRUG
the COOEt rapidly gets hydrolyzed by skin esterases to COOH – ACTIVE FORM
this COOH is important for RAR binding
also, the -S- was introduced as a weak point for metabolism - quickly gets inactivated to s=o and SO2 – this LIMITS SYSTEMIC TOXICITY FROM THE DRUG
true or false
tazarotene is a prodrug
true
what drug is ATRA
does it have selectivity?
tretinoin
no RAR selectivity – it is extremely flexible
true or false
isotretinoin and etretinate are conformationally rigid and selective for specific RARs
FALSE
they are flexible and can cis trans isomerize – not selective. can rotate across alternate single bonds
what drug is 13-cis retinoic acid
isotretinoin
what is the name of the enzymes that allow for cis-trans isomerization in ATRA
retinoid isomerases
Etretinate is a _______ analog
explain
tretinoin/ATRA analog
it just has an ethyl ester added to the end of it – therefore it is a PRODRUG
also, it is NOT RIGID – not selective for RARs
TRUE OR FALSE
all retinoids are teratogenic and should be avoided during pregnancy
true
etretinate seems to accumulate where after repeated dosing?
why?
what does this mean?
in adipose tissue because it’s very lipophilic – therefore, has an EXTREMELY LONG HALF LIFE - 120 days
as mentioned, etretinate has an extremely long half life of 120 days due to its high lipophilicity and distribution into adipose tissue
what about its metabolite?
its metabolite - acitretin - has a much shorter half life of 49 hours because of the hydrophilic COOH group
true or false
the metabolite of etretinate is pharmacologically active
true
explain the general structure of anthralin and what this says about its mechanism of action
planar tricyclic molecule
any molecule like this can slide in between DNA strands and have anti-proliferative effects of skin cells through inhibit DNA synthesis
(sliding is called intercalation)
tapinarof is a structural analog of what?
resveratrol
what class is tapinorof
aryl hydrocarbon receptor agonist
explain the aryl hydrocarbon receptor and where it is widely expressed
cytosolic ligand gated ion channel, widely expressed in the SKIN !! - good target for psoriasis
what is the acronym for the response given by an AhR receptor agonist
AAD response
anti inflammatory
anti oxidant
development and maintenance of skin barrier
explain the MOA of tapinarof
goes through the skin and into the cell where it binds AhR receptor in the cytoplasm
the drug-receptor complex goes to the nucleus and, with the help of an AhR nuclear translocator, gets into the nucleus where it modulates gene transcription
causing dec inflamm cytokines, increased antioxidant response, and increased barrier proteins for the skin
explain TWO WAYS in which tapinarof has antioxidant activity
- by modulating transcription and producing more reducing molecules like GSH and NADPH
- tapinarof is an antioxidant ITSELF due to the phenolic OH”s
name 2 barrier proteins that are increase through the AhR agonist actions of tapinarof
fillagrin
loricin
they cross link to keratin filament to make firm barrier
name 2 psoriasis agents that have a tricyclic planar structure and what this means about their action
anthralin
methoxsalen
both are able to intercalate between DNA strands and inhibit DNA synthesis, having anti-proliferative skin effects
Methoxsalen is used in what treatment?
photochemotherapy for severe psoriasis
a naturally occurring photactive substance that is activated upon exposure to light
true or false
methoxasalen is a synthetic photoactive substance
FALSE – naturally occuring photactive substance
methoxsalen is classified as a ____ or ___ (chemically)
psoralen or furocoumarin
true or false
methoxsalen is given orally
true
the MOA of methoxsalen is______ mediated. be specific
UVA mediated, specifically UVA 320-400nm (broad band)
explain the MOA of methoxsalen
upon exposure to UVA320nm-400nm, there is free redical (1 electron transfer) covalent binding with THYMINE on DNA strands
can be either cross linked (both furan and coumarin bound to thymine) or mono-adducts (only furan or coumarin is bound to thymine)
this binding to thymine on DNA causes decreased DNA synthesis and inhibition of the growth of skin cells
tacrolimus is a ____ isolated from ___
macrolide isolated from fungal strain
explain MOA of apremilast
PDE4 inhibitor
in psoriasis patients, PDE4 is overactive and too much cAMP is being converted to AMP. these low cAMP levels trigger the production of proinflammatory cytokines.
apremilast prevents conversion of cAMP to AMP, thus increasing cAMP levels and, in turn, decreasing the production of proinflammatory cytokines
