PUBLICATION
Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis
- Authors
- Bhuktar, H., Thirupataiah, B., Mounika, G., Samarpita, S., Rithvik, A., Sasi Priya, S.V.S., Naskar, R., Medishetti, R., Jagadish, P.C., Parsa, K.V.L., Rasool, M., Chakraborty, S., Pal, M.
- ID
- ZDB-PUB-240808-4
- Date
- 2024
- Source
- Bioorganic chemistry 151: 107689 (Journal)
- Registered Authors
- Medishetti, Raghavender
- Keywords
- Isoquinolone, PDE4 inhibitors, Psoriasis, Rheumatoid arthritis
- MeSH Terms
-
- Animals
- Arthritis, Experimental/chemically induced
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/pathology
- Arthritis, Rheumatoid*/drug therapy
- Cyclic Nucleotide Phosphodiesterases, Type 4*/metabolism
- Dose-Response Relationship, Drug
- Humans
- Male
- Molecular Docking Simulation
- Molecular Structure
- Phosphodiesterase 4 Inhibitors*/chemical synthesis
- Phosphodiesterase 4 Inhibitors*/chemistry
- Phosphodiesterase 4 Inhibitors*/pharmacology
- Phosphodiesterase 4 Inhibitors*/therapeutic use
- Psoriasis*/drug therapy
- Rats
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 39111119 Full text @ Bioorg. Chem.
Citation
Bhuktar, H., Thirupataiah, B., Mounika, G., Samarpita, S., Rithvik, A., Sasi Priya, S.V.S., Naskar, R., Medishetti, R., Jagadish, P.C., Parsa, K.V.L., Rasool, M., Chakraborty, S., Pal, M. (2024) Targeting next-generation PDE4 inhibitors in search of potential management of rheumatoid arthritis and psoriasis. Bioorganic chemistry. 151:107689.
Abstract
Immune-mediated inflammatory diseases (IMIDs) comprise a broad spectrum of conditions characterized by systemic inflammation affecting various organs and tissues, for which there is no known cure. The isoform-specific inhibition of phosphodiesterase-4B (PDE4B) over PDE4D constitutes an effective therapeutic strategy for the treatment of IMIDs that minimizes the adverse effects associated with non-selective PDE4 inhibitors. Thus, we report a new class of isoquinolone derivatives as next-generation PDE4 inhibitors for effective management of rheumatoid arthritis (RA) and psoriasis. Among the series, 8 compounds i.e. 1e, 1l, 1m, 1n, 1o, 2m, 2o and 3o showed promising PDE4B inhibition (>80 %) in vitro with IC50 ∼ 1.4-6.2 µM. The compound 1l was identified as an initial hit and was pursued for further studies. According to structure-activity relationship (SAR), an allyl group at C-4 position improved PDE4B inhibition. The correlation between in vitro activity data and binding affinities obtained via molecular docking suggested that the high-affinity binding to PDE4B is a prerequisite for the effective inhibition of PDE4B. Notably, the hit 1l showed selectivity towards PDE4B over PDE4D in vitro. Furthermore, 1l treatment (30 mg/kg) in the adjuvant-induced arthritis (AIA) rat model induced by complete Freund's adjuvant (CFA) demonstrated anti-arthritic potential via ameliorating paw swelling and body weight, narrowing joint space, reducing excessive immune cells infiltration and pannus formation in addition to reducing mRNA expression of pro-inflammatory cytokines such as TNF-α and IL-6 in synovial tissues of experimental rats. Additionally, 1l reduced the hyper-proliferative state and colony forming potential of IMQ-induced psoriatic keratinocytes. The treatment of these cells with 1l markedly reduced the protein levels of Ki67 and mRNA levels of pro-inflammatory cytokines e.g. IL-17A and TNF-α suggesting its potent anti-psoriatic potential. Furthermore, 1l did not show any significant adverse effects when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at the tested concentrations (1-100 µM) and the NOAEL (no-observed-adverse-effect level) was found to be 100 µM. Thus, with promising anti-inflammatory effects both in vitro and in vivo along with PDE4B selectivity with an acceptable safety margin, 1l emerged as a new and promising inhibitor for further studies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping