27 - IBD Medchem Flashcards
SAR of H1-Antagonist
What causes a INCREASE in H1 Antagonistic Activity?
PARA** on **AR1
P–>AR1
INCREASE H1 Antagonistic Activity
&
also DECREASES Anticholinergic Side Effects
What IBD Drug?
MoA?
TOFACITINIB
ORAL - Jak3/Jak1 Antagonist
for UC
What IBD Drug?
MoA?
H3 Agonist
(R) a-Methylhistamine, -CH3 @ branch
H3 Receptors present in CNS
What IBD Drug?
MoA?
PENTOXIFYLLINE
SImilar to Thalidomide & Caffeine
Active metabolite is Lisofylline
- down regulates the:*
- *TNF-a production** @ protein & mRNA levels
weaker TNF-a inhibition vs Thalidomide
What is ESSENTIAL for RECEPTOR BINDING?
AdrenoCorticoids
C & D Rings
carbons 11-21 (except 19)
C3 Carbonyl** & **Delta4 Double Bond
What IBD Drug & MoA?
Sulfasalazine = Prodrug
Sulfapyridine = highly lipid soluble
VV
Absorbed from the Colon
Balsalazide is only in Europe
- *1-Ene** of Prednisone / Prednisolone
- *does WHAT?**
Increases:
ANTI-INFLAMMATORY Activity x4
&
Salt Retention, Slightly
What can SIGNIFICANTLY LOWER Mineralcorticoid Activity?
Adrenocorticoids
Adding Substituents to the
A-SIDE
significantly LOWER mineralcorticoid activity
but does not abolish GC activity
What IBD Drug & MoA?
Mesalamine
AminoSalicylate, 5-ASA
Blocking CycloOxygenase
&
Inhibiting Prostaglandin Synthesis @ Colon
Controlled Release formulations:
Target GI location
What Substituents DECREASE Salt Retention?
Glucocorticoids
6a-Methyl
in Methyprednisolone
also INHIBITS CYP oxidation @ C6
16a-OH
16a- / 16b-methyl
SAR of H1-Antagonist
What causes a DECREASE in H1 Antagonistic Activity?
Ortho / Meta on AR1
OM->AR1
or
PARA** on **BOTH AR1+AR2
PARA on BOTH Aromatics
DECREASE H1 ANTAGONISTIC ACTIVITY
Calcineurin Inhibitors
for IBD
Drugs / MoA / Indications
CYCLOSPORINE** // **TACROLIMUS
CSA // FK
- Prevents* Translocation of NFAT to nucleus
- Inhibits:*
- *Transcription of cytokines = IL-2**
Used in:
SEVERE + Treatment-REFRACTORY Cases
What IBD Drug?
MoA?
Thalidomide
SImilar to Pentoxifylline & Caffeine
Accelerates the:
*DEGRADATION* of TNF-a MRNA
inhibits the BIOSYNTHESIS
Still investigational, shown efficacy in
children + adolescents with Refractory Cohns Disease
What IBD Drug?
MoA?
DIPHENHYDRAMINE
FIRST GEN H1 Antagonist
- *Lipophylic –> crosses BBB**
- *CNS Sedation side effects**
H1 Receptor Antagonist
GENERAL STRUCTURE
2 Aromatic Rings
+
Tertiay Amine
Distance is 3-4 carbons away
What IBD Drug?
MoA?
H1 Agonist/Antagonist
2-MethylHistamine, -CH3 @ 2-position
CH3 is BETWEEN the Nitrogens
ANTIHISTAMINE = ALLERGIES
SAR of H1-Antagonist
What causes a DECREASE in H1 Antagonistic Activity?
Ortho / Meta on AR1
OM->AR1
or
PARA** on **BOTH AR1+AR2
PARA on BOTH Aromatics
DECREASE H1 ANTAGONISTIC ACTIVITY
H1 Binding Pocket
4 Components
Bidentate H-Bond
Hydrophobic Pocket
Weakly BASIC Pocket
small hydrophobic pocket
Optimal Distance ~4 carbons
between the Bidentate H-bonding group & Imidazole ring
Terfenadine & Astemizole
Class / ADR
the FIRST Second Generation H1 Antagonist
exhibited:
no CNS sedation & less AC side effects
but….
Metabolized by CYP3A4
VVV
CYP3A4 substrates ketoconazole / clarithromycin
VVV
CARDIAC TOXICITY** & **ARRTHMIAS
due to hERG inhibition
What IBD Drug?
MoA?
AZATHIOPRINE
PRODRUG of 6-MP
- INHIBITS*
- *Purine Nucleotide Biosynthesis**
- T+B-cells lack the salvage pathway*
AzathioPURINE
What IBD Drug?
MoA?
Fexofenadine
2nd Generation H1 Antagonist
- *Carboxylated Active Metabolite of TERFENADINE**
- *= potency & non-sedating**
- LESS drug interactions // elminated unchanged*
SAR of H1-Antagonist
AR2 Binding Site Considerations
HETEROAROMATIC RING
added to AR2 binding site = TOLERABLE
&
PARA** on **BOTH AR1+AR2
PARA on BOTH Aromatics
DECREASE H1 ANTAGONISTIC ACTIVITY
What ABOLISHES Glucocorticoid Activity?
AdrenoCorticoids
Insertion of Substituents on the
B-SIDE
Beta = ABOVE
insertion at the A-SIDE does NOT abolish GC activity
SAR of H1-Antagonist
What causes a DECREASE in H1 Antagonistic Activity?
Ortho / Meta on AR1
OM->AR1
or
PARA** on **BOTH AR1+AR2
PARA on BOTH Aromatics
DECREASE H1 ANTAGONISTIC ACTIVITY
TNF-Alpha Monoclonal AB’s
for IBD
Drugs / MoA
Infliximab** // **Adalimumab
Certolizumab // Golimumab
- *Monoclonal AB’s** that target:
- *TNF-A**
- *important pro-iflammatory Cytokine**
What IBD Drug?
MoA?
H2 ANTAGONIST
4-Methylhistamine, CH3 @ “4-Position”
CH3 is next to the longer Chain
- Inhibits:*
- *Gastric Acid Secretion**
What IBD Drug?
MoA?
LORATADINE
2nd Generation H1 Antagonist
Metabolized by CYP3A4
Similar structure to 1st Gen Diphenhydramine
HAS LINKED Aromatics = Not freely rotating
Desloratadine
= more broken down, less CYP3A4 metabolism
What IBD drug & MoA?
Olsalazine
Aminosalicylate, 5-ASA
Dimer of 5-ASA linked by an AZO Bond
converted into ASA by:
Bacteria @ Lower Intestine
PRODRUG
What IBD Drug?
MoA?
METHOTREXATE
Folic Acid Analog
INHIBITS
Pyrimidine Biosynthesis
MTX = PYR
What IBD Drug?
MoA?
CETIRIZINE
Oxidized Active metabolite of Hydroxyzine = potency
less drug interactions // eliminated unchanged
Similar structure to 1st Gen Diphenhydramine
but with cyclic Nitrogen
