Med Chem

Question 1

Bosentan (Tracleer)

Answer 1

• 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

Question 2

Ambrisentan (Letairis)

Answer 2

• 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

Question 3

Macitentan (Opsumit)

Answer 3

• 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

Question 4

Nitric Oxide (INOmax)

Answer 4

• 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

Question 5

Sildenafil Citrate (Revatio)

Answer 5

• 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

Question 6

Tadalafil (Adcirca)

Answer 6

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

Question 7

Riociguat (Adempas)

Answer 7

• 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

Question 8

Prostacyclin

Answer 8

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

Question 9

Epoprostenol (Flolan)

Answer 9

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

Question 10

Treprostinil (Remodulin)

Answer 10

• 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

Question 11

Iloprost (Ventavis)

Answer 11

• 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

Question 12

Selexipag (UPTRAVI)

Answer 12

• 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