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Flashcards in Med Chem Deck (12):
1

Bosentan (Tracleer)

- a pyrimidine/sulfonamide ETRA
- competitive antagonist
- ETa (higher affinity & ETb
- T 1/2 approx 5 h. & highly protein bound ( > 98%)
- induces CYP2C9
- active metabolite- (10-20% of Bosentan's activity)
- Liver injury & teratogenicity
--> blocks bile acid transport in the liver & allows bile acids to accumulate in hepatocytes

2

Ambrisentan (Letairis)

- a pyrmidine/carboxylic acid ETRA (pka- 4.0)
- insoluble in H2O @ low pH, solubility increase @ higher pH
- > 77 fold ETa selectivity
- rapidly absorbed & 99% protein bound
- effective t 1/2 of 9 h.
- teratogenic/potential liver injury
- metabolized by CYP3A4, 2C19 & UGTs
--> can convert this to a salt to make more soluble in H2O

3

Macitentan (Opsumit)

- a pyrimidine/sulfamide ETRA
- non-selective antagonist for ETa & ETb
- is de-propylated by CYP3A4 to an active metabolite (accounts for 40% of Opsumit's total activity)
- 50% eliminated in urine
- teratogenic

4

Nitric Oxide (INOmax)

- an uncharged gas for inhalation
- direct replacement for endogenous NO
- activates sGC and increases cGMP levels= muscle relaxation
- Short DOA: rapid metabolism to Nitrate ion
- readily diffuse through vascular smooth muscle (lipophilic)
--> has resonance structures

5

Sildenafil Citrate (Revatio)

- selective inhibitor of PDE5
- PDE5 role: degradation of cGMP (key for SM relaxation)
- prolongs cGMP activity in pulmonary vascular SM cells
- rapidly absorbed after PO admin. (41% BA)
- T 1/2 approx 4 h.
- 96% bound to plasma proteins
- CYP3A (maj route) & CYP2C9 (minor route)
- N-desmethyl active metabolit: Selective for PDE (50% potent), accounts for 20% of sildenafil's activity
--> purine derivative

6

Tadalafil (Adcirca)

- selective inhibitor of PDE5
- PO admin
- T 1/2 approx 17.5 h.
- 94% bound to plasma proteins
- metabolized by CYP3A4
--> indole derivative

7

Riociguat (Adempas)

- pyrimidine "NO-sGC-cGMP" pathway activator
- increase sGC affinity for NO (NO binds & cat. cGMP synthesis)--> relies on endogenous NO
- also stimulates sGC w/out NO by increasing cGMP
- CYP1A1 forms a less active maj. metabolite
- plasma con. in smokers decrease by 50-60% compared to non-smokers
- co-admin w/CYP inhibitors may lead to hypotension
- teratogenic

8

Prostacyclin

- levels are reduced in PAH state
- endofenous antagonsit of TxA2 ( vasoconstrictor)
- potent vasodilator

9

Epoprostenol (Flolan)

- Na salt of protacyclin
- reconstituted-glycine buffer @ pH 10-11
- stability:

10

Treprostinil (Remodulin)

- synthetic and stable (5 yr @ rt) from of prostacyclin
- admin: PO, inhalation, IV, SC
- rapidly absorbed (100% BA)
- mean T 1/2= 85 min (4-6 h. vasodilation)
- 5 metabolites are known, but metabolic enzymes are UNKNOWN
- 79% of the dose is excreted in urine

11

Iloprost (Ventavis)

- synthetic analog of prostacyclin (PGI2)
- 16S-isomer is 5x > 16R-isomer
- Iloprost dilates arterial vascular beds (systemic & pulmonary)
- stable @ r.t. (t 1/2 of 30 mins)
- 60% protein bound
- Iloprost is approx 10x more potent than prostacyclin
- local activity= coats onto lung aveoli
- metabolized primarily via Beta-oxidations to inactive compds.
--> dinor iloprosts, tetranor iloprst (maj. metabolite) & conjugates
--> sequential loss of acidic acid= beta oxidation

12

Selexipag (UPTRAVI)

- prostacyclin (IP) receptor agonist
- rapidly absorbed after PO and hydrolyzed to active metabolite (metabolite is maj. contributor to overall activity)
- parent drug & active metabolite- highly protein bound 99%
--> structurally dissimilair prostanoid
--> pyrizine