Adenine derivatives substituted in position 9 are important pharmacologically active compounds. Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) inhibits adenosine deaminase and a specific phosphodiesterase (PDE) isozyme. The 9-benzyladenine derivative BWA78U possesses potent anticonvulsant, anxiolytic, and sedative properties but shows weak interaction with benzodiazepine receptors and no binding to A1 and A2 adenosine receptors. Thus, we evaluated the capacity of BWA78U and its analogues to inhibit PDE3 and PDE4. The 2-substituted 6-chloropurines were synthesized from hypoxanthines, alkylated to obtain 9-substituted isomers, and treated with amines to yield adenines. The IC50 values of these compounds on PDE3 and PDE4 from vascular smooth muscle were determined. Some compounds exhibit potent PDE inhibition with high selectivity toward PDE4. For example, compound 6d (NCS 613) shows an IC50 of 0.04 µM for PDE4 and 380 µM for PDE3, demonstrating high selectivity. Structure-activity relationship (SAR) analysis indicates that substituents on the adenine ring, including a methyl group at position 6, a benzyl group at position 9, and a trifluoromethyl group at position 2, are crucial for potency. These compounds are a novel class of PDE4 inhibitors, providing an efficient tool for studying PDE4 inhibition. Further work on detailed SAR analysis, pharmacophore identification, and in vivo pharmacological properties will help understand their mechanism of action, especially related to central nervous system (CNS) effects.