# Polynitrogen Bicyclic and Tricyclic Compounds as PDE4 Inhibitors
## 1 Introduction  
Phosphodiesterases (PDEs) are a family of enzymes responsible for the hydrolysis of the intracellular cyclic nucleotides adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP), causing their inactivation [1, 2]. Currently, eleven PDE subfamilies (PDE1-PDE11) and at least twenty-one isoforms with numerous splice-site variants are known in humans, which are characterized by different functional roles, tissue distribution, and substrate specificity (cAMP/cGMP) [3]. The PDE4 subfamily, specific for cAMP, is encoded by four genes (A-D), translating into four isoforms: PDE4A-PDE4D [4, 5]. These are found in several cell types and tissues, including airway, pulmonary and vascular smooth muscle, vascular endothelium, and brain [6]. Moreover, PDE4A, PDE4B, and PDE4D are additionally expressed in immunocompetent and inflammatory cells, as neutrophils, T-lymphocytes, macrophages, and eosinophils [7]. It is well known that the increase in intracellular cAMP concentrations by PDE4 inhibition affords a potent anti-inflammatory effect, useful for interfering with a broad range of diseases, including asthma, chronic obstructive pulmonary disease (COPD), Crohn's disease, psoriasis, atopic dermatitis, and rheumatoid arthritis [8, 9]. In recent years, other possible therapeutic applications have also emerged for PDE4 inhibitors, and relate to neurological disorders such as depression,Alzheimer's disease, and anxiety, with some compounds currently in clinical trials for these pathologies [10; 11; 12]. Since 2010, four PDE4 inhibitors have been launched on the market (Figure 1). Firstly Roflumilast (DaxasTM, AstraZeneca, Cambridge, UK) for COPD [13], then Appremilast (Celgene; 2014, Summit, NJ, USA) for psoriasis [14; 15] and, lastly, Ibudilast (Medicinova; 2016, La Jolla, CA, USA) for Krabbe Disease [16] and Crisaborole (Pfizer; 2016, New York, NY, USA) for atopic dermatitis [17], were commercialized. From the 1990s, we have been working in the field of PDE4 inhibitors, obtaining very interesting results in terms of developing several new hits endowed with high potency and selectivity [18; 19]. Recent outcomes of this research [20] have focused on fragment-based drug design (FBDD) strategies [21] to identify new quinoline-based PDE4 inhibitors as an evolution of GSK-256066, one of the most potent PDE4 inhibitors synthesized to date (IC\({}_{50}\) = 8 pM), in clinical trials for COPD and asthma [22]. The structure-activity relationships (SARs) of this latest series have been finely assigned, and the most relevant results in terms of PDE inhibition are outlined in Figure 2, along with the most favorable groups and functions determining the activity [20]. To continue our investigation on the quinoline scaffold towards PDE4 inhibition, we have adopted compound **A** (**Se** in the original paper [20], i.e., the most active product of the series, IC\({}_{50}\) = 21.27 nM) (Figure 3) as the lead candidate, in order to plan the synthesis  
Figure 1: Approved PDE4 inhibitor drugs. Figure 2: Biological activity and relevant substituents within the previous quinoline-based PDE4 inhibitor series. of new amide derivatives, by (1) introducing de novo an amide function in meta position of the aniline group (indicated as red circles) and (2) elaborating the primary amide at position 3 of the heterocyclic scaffold (indicated as blue circle) (Figure 3). The choice of inserting an additional amide group on the 3-methoxyaniline in position 4 results from the observation that a limited number of compounds developed earlier and bearing a secondary alkylaryl amide in this position possess an activity in the micromolar range [20], while the primary amide is completely inactive. With regard to the rationale behind modifying the primary amide at position 3 of the quinoline, we have previously developed compound **B** (**9** in the original paper [20]), bearing the \(N\)-(3,5-dichloropyridin-4-yl)amide fragment of Rolfumilast.