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Novel Inhibitors of PDE5

 Phosphodiesterase is a enzyme selectively catalyzes the hydrolysis of the 3’ cyclic phosphate
bonds of adenosine and/or guanosine 3′,5′-cyclicmonophosphate into their respective 5´-
nucleosidemonophosphates.

Introduction to PDE

 Phosphodiesterases (PDEs) play a critical role in maintaining the cellular level of cyclic adenosine
monophosphate (cAMP) and cyclic guanosine monophosphate. cAMP and cGMP are second
messengers that mediate biological responses to a variety of extracellular cues, including hormones,
neurotransmiters, chemokines, and cytokines

 Increased concentration of these cyclic nucleotides results in the activation of protein kinase A and
protein kinase G. These protein kinases phosphorylate a variety of substrates, including transcription
factors and ion channels, which regulate a myriad of physiological processes, such as immune
responses, cardiac and smooth muscle contraction, visual response, glycogenolysis, platelet
aggregation, ionchannel conductance, apoptosis, and growth control.
 There are now 11 phosphodiesterase families, many of which exist as splice variants. The cAMP-
specific enzymes include phosphodiesterase 4 (PDE4),-7and -8. The cGMP-specific PDEs are
PDE5,-6 and -9, whereas PDE1,-2,-3,-10 and -11 use both cyclic nucleotides.

 Each family typically having several different isoforms and splice variants. These unique PDEs
differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular
localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual
isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the
opportunity for selectively targeting specific PDEs for treatment of specific disease states
• phosphodiesterase type 5 (PDE5), mostly distributed in smooth muscle and found in corpus
cavernosum,heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach, is responsible
for specifically cleaving the second messenger, cyclic guanosine monophosphate (cGMP).

• PDE5 is a dimer of identical subunits each with Mr of ~95,000–100,000 .A regulatory domain is
located in the amino-terminal portion of each monomer, and a catalytic domain occupies the more
carboxyl-terminal region..

• The regulatory,catalytic domains are highly specific for cGMP and, like all known PDEs, contains
a binuclear metal-binding site occupied by divalent cations (zinc and another divalent cation,
presumably magnesium or manganese) that are required to support catalys.


Introduction to PDE5
• Inhibitors of PDE5 prevent the hydrolysis of cGMP, leading to their potential to treat the diseases
associated with low cGMP levels. PDE5 is thus a prime target for the development of inhibitors
which have served as drugs in the treatment of male erectile dysfunction (MED), cardiovascular
diseases pulmonary arterial hypertension (PAH),and lower urinary tract symptoms (LUTS) in
men with benign prostatic hyperplasia (BPH).
Fig 3. Commercial PDE-5 inhibitors
• Despite deficiencies with these inhibitors, such as the lack of sufficient selectivity against other
PDE isozymes, most notably PDE6 or PDE11, it has been proved that the inhibition of PDE5 is an
effective therapy for the diseases mentioned above and there is continuing interest in discovering
novel PDE5 inhibitors.
 The solved crystal structures of the PDE5 catalytic domain in complex with different inhibitors
have revealed the characteristic binding interactions of inhibitors with the enzyme.

 These include mono- or bidentate hydrogen bonds (H-bonds) between inhibitors and the residue
Q817, hydrophobic interactions, in particular the π−πstacking interactions between the aromatic
rings of inhibitors and the hydrophobic clamp mainly composed of residues V782 F786 and
F820, and occasionally interactions also formed between inhibitors and two metal ions (Zn 2+
and Mg 2+ in most cases) coordinated at the active site of the catalytic domain.