Med chem part 6 Flashcards
______ is a structural analog of folic acid
methotrexate
the active form of methotrexate is…..
polyglutamate - has multiple (5) glutamates oh Y-COOH
what enzyme does methotrexate inhibit?
DHFR (dihydrofolate reductase)
how does methotrexate work as an immunosuppressant?
inhibits DHFR (dihydrofolate reductase, which in turn inhibits de novo synthesis of thymidine)
doing this prevents the conversion of folate to THF (tetrahydrofolate) which is involved in the conversion of uridine to THYMIDINE, which are involved in DNA/RNA synthesis, respectively
thus, proliferation of T and B immune cells is inhibited, including those responsible for synovial inflammation
true or false
methotrexate is a potent immunosuppressant
true
methotrexate is said to have ________ properties.
why?
antifolate
prevents conversion of folate to THF by inhibiting dihydrofolate reductase
what does the “tetra” in tetrahydrofolate mean
2 double bonds have been reduced
“dihydro” what does di mean
1 double bond has been reduced
what is a major side effect of methotrexate?
may cause dose-dependent folate deficiency
true or false
folate deficiency, induced by methotrexate, does not respond well to replacement therapy
false - it does
why is administering NSAIDS and methotrexate TOGETHER not advised?
they compete for the same transporter to be excreted
can lead to accumulation and toxic effects of methotrexate
how is methotrexate excreted?
through what transporter?
what else is excreted via this transporter?
excreted unchanged
through folate transporter (human organic anion transporter)
NSAIDS are also excreted with this
as mentioned, NSAIDS and MTX compete for the same transporter to be excreted
why is it that this leads to toxic levels of MTX and not NSAIDS?
because MTX is highly potent.
thus, there is much more NSAID and more likely to saturate the transporters, leaving MTX accumulating in the blood
aside from inhibiting DHFR, what other minor components of MTX MOA are there?
-increase adenosine levels and receptor activation, leading to decreased inflammation
-inhibit synthesis of polyamines which accumulate in synovial fluid and produce toxic ammonia and H2O2 through metabolism. they also activate NFKB (“on” switch for inflammation)
as mentioned, MTX inhibits the synthesis of polyamines
these include what 2 things and what do they do?
spermine and spermidine
they produce toxic ammonia and peroxide through their metabolism in the synovial fluid
AND activate NFKB (“on” switch for inflammation)
thus, MTX inhibiting the synthesis of spermine and spermidine prevents these things from happening
blocking what signaling pathway would have antirheumatic effects?
name 4 drugs that are involved with inhibiting this pathway
JAK STAT pathway
Tofacitinib
Baricitinib
Upadacitinib
in general, what are JAK inhibitors called
jakinibs
explain how the JAK STAT pathway works
cytokine binds to receptor and it dimerizes
the tyrosine residues on JAKS and the receptor itself gets phosphorylated
STAT binds to this complex and undergoes phosphorylation too – TRANSLOCATES TO NUCLEUS where it transcribes the target genes — in this case the transcription of inflammatory genes that produce cytokines
name 3 ways in which the JAK STAT pathway can be blocked
bind the cytokine (monoclonal antibodies)
bind to the receptor
block JAK (this is what jakinibs do!!) and prevent activation/phosphorylation of stat
name the first in class JAK1 SELECTIVE INHIBITOR
Upadacitinib
what is an important component of JAK inhibitors, and kinase inhibitors in general?
have 2 hydrogen bonds
1 part on the molecule (sp2) acts as an acceptor and the other part (sp3) acts as a donor
what is the first in class JAK1/JAK3 inhibitor
tofacitinib
JAK1/JAK2 selective inhibitor
Baricitinib
cytokines ___ and ____ are KEY mediators of immune function in RA and have been major targets of therapies
IL-6 and TNFa
name 2 IL-6 blockers
are they biologics?
tocilizumab
sarilumab
yes
how do the IL-6 blockers, Tocilizumab and Sarilumab, work?
they bind to the IL-6 RECEPTOR and inhibit IL-6 mediated signaling
which IL-6 inhibitor requires higher dose and frequency to achieve the same effects as the other?
why?
tocilizumab
it is less potent than sarilumab
name a T-cell costimulatory inhibitor
is it synthetic or a biologic?
biologic
abatacept
explain the MOA of Abatacept
why is it called a “costimulatory” inhibitor
it blocks CD28 on the T cell from binding to both CD80 AND CD86 on the antigen presenting cell
thus, it regulates the second signal required for full T cell activation
as mentioned, Abatacept modulates the SECOND costimulatory signal required for full T cell interaction
what is the first?
T cell interaction with MHC complex
what is the function of Rituximab?
is it synthetic or biologic?
biologic
mediates B cell apoptosis by binding to CD20 on the B cell
explain the mechanism of action how corticosteroids are used for rheumatoid arthritis
glucorticoids stimulate the synthesis of LIPOCORTIN
this inhibits PLA2 – which cleaves arachidonic acid from membranes - 1st step in prostaglandin synthesis
blocks production of prostaglandins through COX AND leukotrienes through LOX
what is another name for lipocortin
Annexin A1
which is a more effective/potent anti inflammatory: steroids or NSAIDS?
STEROIDS!!
blocks production of both prostaglandins AND leukotrienes
NSAIDS just block prostaglandins
COX is to prostaglandins as _____ is to leukotrienes
LOX
besides having anti inflammatory effects, name 3 other effects of corticosteroids
anti-mitotic
immunosuppressant
vasoconstriction
how are corticosteroids immunosuppressants?
how are they vasoconstrictors?
immunosuppressants because they suppress the maturation/differentiation/proliferation of immune cells inc dendritic cells and macrophages and inhibits cytokines
vasoconstrictors bc they reduce blood flow to inflamed site to dc # inflamm mediators being delivered
name the 5 required groups for glucocorticoid activity of a steroid
keto at 3
double bond between carbons 4 and 5 in ring A
11 position beta hydroxy
17 position alpha hydroxy
21 position hydroxy
from hydrocortisone molecule, what was added to make prednisolone
a double bond was added between carbons 1 and 2
name the delta 1 corticosteroids
why are they called this?
prednisolone and prednisone
because they have a double bond at carbon 1
what is the only change when looking at the structures of hydrocortisone and prednisolone?
in prednisolone, there is an added double bond between carbons 1 and 2
as mentioned, the only difference between hydrocortisone and prednisiolone is the added double bond between 1 and 2 in prednisolone
what is the result of this
LONGER DURATION OF ACTION
due to increased metabolic stability towards reductions —- bc increased resonance
which is more potent glucocorticoid - prednisolone or prednisone? why?
the OH (alcohol) group at position 11 is ESSENTIAL for glucocorticoid activity
prednisone has a ketone there instead
what occurs when ring A is flattened in corticosteroids
glucocorticoid action increases and mineralcorticoid action decreases
what is a side effect of corticosteroids?
it is due to what action?
retention of sodium and water
due to mineralcorticoid activity
what is the only difference between the delta1 corticoids and triamcinolone?
what was the result of this?
what was then done?
adding a 9 alpha fluorine group and 16 alpha hydroxyl
however, this has poor bioavailability because it is too hydrophilic
bexamethasone and betamethasone were created to address this
as mentioned, dexamethasone and betamethasone were created to address the poor bioavailability of triamcinolone due to the 16 hydroxyl group.
what was done to triamcinolone to create betamethasone and dexamethasone?
instead of a hydroxyl group, a methyl group was inserted at carbon 16
in dexamethasone, the configuration is alpha and in betamethasone it is beta
–only difference between the 2
as mentioned ,the only difference between triamcinolone and dexamethasone/betamethasone is the replacement of a hydroxyl group with a methyl group
what is the result of this?
increased lipophilicity, and thus increased antirheumatic properties
true or false
16-CH3 OR 16-OH leads to increased glucocorticoid activity and decreased minerolocorticoid activity
TRUE
only issue is that OH is too polar and not well absorbed
how is it that adding a 9a-halogen (in the case of hydrocortisone -> betamethosone) increases glucocorticoid activity?
because of electron withdrawing effects on the 11 beta OH — makes it a strong hydrogen bond donor (more acidic properties)
