Synthesis, Pharmacological Profile and Docking Studies of New Sulfonamides Designed as Phosphodiesterase-4 Inhibitors

Abstract

Prior investigations showed that increased levels of cyclic AMP down-regulate lung inflammatory changes, stimulating the interest in phosphodiesterase (PDE)4 as therapeutic target. Here, we described the synthesis, pharmacological profile and docking properties of a novel sulfonamide series (5 and 6a-k) designed as PDE4 inhibitors. Compounds were screened for their selectivity against the four isoforms of human PDE4 using an IMAP fluorescence polarized protocol. The effect on allergen- or LPS-induced lung inflammation and airway hyper-reactivity (AHR) was studied in A/J mice, while the xylazine/ketamine-induced anesthesia test was employed as a behavioral correlate of emesis in rodents. As compared to rolipram, the most promising screened compound, 6a (LASSBio-448) presented a better inhibitory index concerning PDE4D/PDE4A or PDE4D/PDE4B. Accordingly, docking analyses of the putative interactions of LASSBio-448 revealed similar poses in the active site of PDE4A and PDE4C, but slight unlike orientations in PDE4B and PDE4D. LASSBio-448 (100 mg/kg, oral), 1 h before provocation, inhibited allergen-induced eosinophil accumulation in BAL fluid and lung tissue samples. Under an interventional approach, LASSBio-448 reversed ongoing lung eosinophilic infiltration, mucus exacerbation, peribronchiolar fibrosis and AHR by allergen provocation, in a mechanism clearly associated with blockade of pro-inflammatory mediators such as IL-4, IL-5, IL-13 and eotaxin-2. LASSBio-448 (2.5 and 10 mg/kg) also prevented inflammation and AHR induced by LPS. Finally, the sulfonamide derivative was shown to be less pro-emetic than rolipram and cilomilast in the assay employed. These findings suggest that LASSBio-448 is a new PDE4 inhibitor with marked potential to prevent and reverse pivotal pathological features of diseases characterized by lung inflammation, such as asthma.

Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease

“…To evaluate whether these tadalafil derivatives retained PDE5 inhibition, an IMAP-FP (immobilized metal ion affinity-based fluorescence polarization) assay , was conducted using tadalafil as a reference. Compounds ( 1p , q , 1v , w , 2b – e , 2i – k , 2m , n , and 2q ) with good AChE inhibition (IC 50 < 1 μM) were selected to determine the PDE5 inhibitory activity to identify good dual-target AChE/PDE5 inhibitors, and the results are shown in Table .…”

Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5)

“…Following, an IMAP-FP (immobilized metal ion affinity-based fluorescence polarization) assay , was conducted to evaluate the PDE5 inhibitory activities of these tadalafil derivatives with good AChE inhibition (IC 50 < 1 μM), using tadalafil as a reference, and the results are shown in Table . These data showed that most of the tested compounds could retain PDE5 inhibition, with IC 50 values of 0.050–3.231 μM.…”

The Magic Methyl and Its Tricks in Drug Discovery and Development

“…Barbosa and colleagues [46] described a series of combretastatin A-4 analogs based on the N-acylhydrazone (NAH) LASSBio-1586 (54) with cytotoxic and antimitotic activity (Figure 14). Homologation [9] studies on the amide nitrogen led to the benzyl homolog of LASSBio-1586 (54), LASSBio-2070 (56), which showed microtubule-stabilizing behavior, while the methylated homolog, LASSBio-1735 (55), had microtubule-destabilizing behavior.…”