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. 2025 May 28;16(6):1058-1065.
doi: 10.1021/acsmedchemlett.5c00108. eCollection 2025 Jun 12.

Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation

Shin-Young Park  1 , Dang Pham  1 , Param Shukla  1 , Justin Edward  1 , Reshmi John  1 , Addison Li  1 , Michael Hadjiargyrou  1 , Mattia Mori  2 , Elisa Zuccarello  3   4 , Ottavio Arancio  3   4   5 , Jole Fiorito  1   4
Affiliations

Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation

Shin-Young Park et al. ACS Med Chem Lett. .

Abstract

Phosphodiesterase 5 (PDE5) inhibitors have been suggested as new treatments for Alzheimer's disease (AD) and other conditions such as cancer and cardiovascular diseases. Utilizing the widespread presence of the indole moiety in biomolecules and drugs, previously synthesized quinoline and naphthyridine compounds were modified into novel indole-containing PDE5 inhibitors. Replacing the amine with an amide group led to identifying a potent analogue, compound 14a, with an IC50 of 16.11 nM. Molecular docking simulations further highlight the significance of the amide group in drug-target interactions. A cytotoxicity test and a parallel artificial membrane permeability assay validated the compound's potential as a lead for further drug development. Compound 14a was shown to be safe and blood-brain barrier permeable. The discovery of these indole-containing PDE5 inhibitors provides new perspectives for developing PDE5 therapeutics.

Keywords: Alzheimer’s Disease; Indole-containing Molecules; PDE5; PDE5 Inhibitors.

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