Phosphodiesterase Inhibitors

What are the 2 main PDE-4 inhibitors?

1. Cilomilast

2. Piclamilast

Endogenous ligands have a donor and acceptor that bind to glutamine? How do PDE4 inhibitors work?

Have 2 oxygens that are both acceptors

How do the oxygen acceptors in PDE4 bind?

Catechol interacting in bidentate fashion with Gln

Pharmacophore of PDE4 inhibitors

2 oxygens acceptors, hydrophobic group, and metal binding

What molecule is the origin of PDE4 inhibitors?

Rolipram

What are the three zinc binders found in PDE4 inhibitors?

1. Carboxylic acid

2. Pyridine

3. Amide

Discuss the pharmacophores of apremilast?

1. Catechol → binds invariant glutamine

2. Metal binding region (amide)

3. Hydrophobic Pocket

Difference in structure between vardenafil and sildenafil?

1. V: imidazole

2. S: pyrazole

3. Sildenafil double bond may tautomerize

Precusor of sildenafil?

Zaprinast

Name the major regions of sildenafil (invariant glutamine binding, Lid region, metal region)

1. Invariant glutamine (bidentate)

2. Hydrophobic pocket

3. Lid region

4. Zinc binding (H bond water network)

Major side effect of sildenafil? Due to what interaction?

1. Tinted blue vision (cyanopsia)

2. Common green to blue shift

3. Inhibition of PDE6

What is the best PDEVi?

Tadalafil (cialis)

What heterocycle does tadalafil contain? What amino acid?

Diketopiperazine, tryphophan

How is binding of invariant glutamine different in tadalafil?

1. Engaged only via a monodentate interaction

How important is the diketopiperazine in the pharmacophore of tadalafil?

Can be completely removed or replaced with other heterocycles

Describe the lid and metal region in tadalafil?

No lid region or metal binding

Discuss the activity based on the NH?

The NH is REQUIRED for activity

Metabolism of tadalafil?

1. CYP3A4

2. COMT

3. Soft spot = middle of constrained catechol

DDIs of tadalafil?

1.. CYP3A4 (cannabidiol, grapefuit)

2. Organic nitrates

3. Entacapone (COMTi)