Abstract
The natural product icariin inhibits human phosphodiesterase-5 (PDE5) and represents a unique pharmacophore for treating erectile dysfunction, pulmonary hypertension, and other diseases. In this study, we explore the available icariin-derived chemical scaffolds through medicinal chemistry to develop novel icariin PDE5 inhibitors with improved potency and specificity. We synthesized six novel semi-synthetic icariin analogs as well as three naturally occurring icariin analogs, and characterized the structure-activity relationship in the context of human PDE5 inhibition using in vitro enzyme inhibition and kinetics assays and molecular modeling. Mammalian-cell-based assays and in vitro enzyme inhibition assays against human PDE6C further helped to identify the most potent and selective icariin analogs. Our results reveal the synergistic contribution of functional groups at the C3 and C7 positions of the icariin backbone towards PDE5 inhibition. Whereas a hydrophobic and flexible alkanol group at the C7 position is sufficient to enhance icariin analog potency, combining this group with a hydrophilic sugar group at the C3 position leads to further enhancement of potency and promotes specificity towards PDE5 versus PDE6C. In particular, compounds 3 and 7 exhibit Ki values of 0.036 ± 0.005 μM and 0.036 ± 0.007 μM towards PDE5 respectively, which are approaching those of commercial PDE5 inhibitors, and can effectively reduce GMP levels in cultured human BJ-hTERT cells. This study identifies novel icariin analogs as potent and selective PDE5 inhibitors poised to become lead compounds for further pharmaceutical development.
Highlights
Cyclic nucleotide phosphodiesterases (PDEs) are key regulators of intracellular levels of the ubiquitous second messenger molecules cyclic guanosine monophosphate and cyclic adenosine monophosphate in eukaryotes [1,2]. cGMP and cAMP are biosynthesized from their corresponding nucleoside triphosphates (NTPs) by specific nucleotidyl cyclases in response to upstream signals, such as hormones or neurotransmitters, and modulate a variety
Using a series of naturally occurring and novel semi-synthetic icariin analogs, we explored the structure-activity relationships between PDE5 inhibition and the icariin pharmacophore
In vitro inhibition assays revealed that while a flexible, linear, hydrophobic group at the 7-O position is sufficient to increase PDE5 inhibition potency by up to 43-fold compared to icariin, the 3-O and 7-O positions can act synergistically to improve the potency of PDE5 inhibition up to 72-fold compared to icariin
Summary
Cyclic nucleotide phosphodiesterases (PDEs) are key regulators of intracellular levels of the ubiquitous second messenger molecules cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in eukaryotes [1,2]. CGMP and cAMP are biosynthesized from their corresponding nucleoside triphosphates (NTPs) by specific nucleotidyl cyclases in response to upstream signals, such as hormones or neurotransmitters, and modulate a variety. Cyclic nucleotide phosphodiesterases (PDEs) are key regulators of intracellular levels of the ubiquitous second messenger molecules cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) in eukaryotes [1,2]. cGMP and cAMP are biosynthesized from their corresponding nucleoside triphosphates (NTPs) by specific nucleotidyl cyclases in response to upstream signals, such as hormones or neurotransmitters, and modulate a variety
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