2. Academic Validation
  3. Design and development of potent roflumilast analogues targeting PDE-4B: selectivity and pharmacokinetic insights

Design and development of potent roflumilast analogues targeting PDE-4B: selectivity and pharmacokinetic insights

  • Bioorg Chem. 2025 Dec:167:109201. doi: 10.1016/j.bioorg.2025.109201.
Ahmed M Moussa 1,  Heba Abdelrasheed Allam 2,  Ahmed A Al-Karmalawy 3,  Abdelrahman K Salem 4,  Radwan Alnajjar 5,  Sally T Mahmoud 6,  Marwa A Fouad 7,  Mohamed K El-Ashrey 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.; Department of Pharmaceutical Chemistry, College of Pharmacy, The University of Mashreq, Baghdad 10023, Iraq.
  • 4 Pharmaceutical Chemistry Department, School of Pharmacy, Newgiza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
  • 5 Department of Chemistry, Faculty of Science, University of Benghazi, Benghazi, Libya.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.; Pharmaceutical Chemistry Department, School of Pharmacy, Newgiza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.; Pharmaceutical Chemistry Department, School of Pharmacy, Newgiza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt.. Electronic address: [email protected].
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.; Medicinal Chemistry Department, Faculty of Pharmacy, King Salman International University, South Sinai 46612, Egypt.
PMID: 41205475 DOI: 10.1016/j.bioorg.2025.109201
Abstract

Phosphodiesterase-4B (PDE4B), a key regulator of intracellular cAMP degradation, has emerged as a compelling therapeutic target due to its involvement in various diseases, such as inflammation, COPD, schizophrenia, Cancer, and cardiac disorders. Two series of acid hydrazide derivatives (4a-i and 5a-f), along with compounds 6 and 7, were designed, synthesized, and evaluated for their PDE4B inhibitory activity. Compounds 4i and 4f showed the highest potency (IC₅₀ = 7.42 and 8.30 nM, respectively), with no statistically significant difference from the reference drug roflumilast (IC₅₀ = 2.36 nM; p < 0.05). Selectivity studies revealed that compounds 4f and 4i were ∼2.6- and ∼2.0-fold more selective for PDE4B over PDE4D, respectively, comparable to roflumilast (∼3.0-fold). Compound 4f demonstrated ∼340- and ∼307-fold selectivity for PDE4B over PDE4A and PDE4C, respectively, while 4i showed ∼195- and ∼169-fold selectivity; in contrast, roflumilast exhibited markedly lower selectivity, with only ∼26-fold over PDE4A and ∼59-fold over PDE4C. Functional assays showed that 4i achieved the greatest cAMP elevation (3.63 ± 0.30 pmol/mL) and TNF-α inhibition (64.59 %), though still lower than roflumilast (8.40 ± 0.79 pmol/mL; 81.58 %). Compounds 4f and 4i (IC₅₀ = 57.15 and 69.33 μM, respectively) exhibited notable DPPH radical scavenging activity close to roflumilast (IC₅₀ = 41.87 μM) and ascorbic acid (IC₅₀ = 40.65 μM). In WI-38 normal lung fibroblasts, compound 4i (IC₅₀ = 91.01 μM) showed cytotoxicity comparable to roflumilast (IC₅₀ = 109.71 μM), while 4f (IC₅₀ = 151.50 μM) was less cytotoxic. Both compounds were markedly safer than staurosporine (IC₅₀ = 35.58 μM), with 4f displaying the best safety profile. Molecular docking revealed that the tested compounds 4f and 4i exhibited higher docking scores and similar binding modes to roflumilast, which were further confirmed by molecular dynamics simulations for 200 ns. Additionally, 4f and 4i showed enhanced metabolic stability with longer in vitro half-lives (70.01 and 198.04 min, respectively) and lower intrinsic clearance rates (20.04 and 7.04 mL/min, respectively) compared to roflumilast (56.81 min; 24.69 mL/min). Both compounds displayed greater stability in human plasma and simulated gastrointestinal fluids. Equilibrium dialysis technique revealed that compound 4i had plasma protein binding comparable to roflumilast (93.01 % vs. 94.80 %), whereas 4f showed the lowest binding percentage at 77.24 %, indicating better accessibility for tissue distribution. Overall, this work highlights selective PDE-4B inhibitors as a compelling direction for future COPD therapies.

Keywords

Chronic obstructive pulmonary disease; Molecular dynamics; Pharmacokinetics; Phosphodiesterase 4B inhibitor; Roflumilast analogues.

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