Substituted furans as inhibitors of the PDE4 enzyme

The synthesis and in vitro activity of a series of substituted furans as a novel structural class of PDE4 inhibitors is described. Comparison of emetic threshold with known PDE4 inhibitors is presented.     

Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors

Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure–activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.     

Design, synthesis, and biological evaluation of 8-biarylquinolines: a novel class of PDE4 inhibitors

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.     

Discovery of a substituted 8-arylquinoline series of PDE4 inhibitors: structure-activity relationship, optimization, and identification of a highly potent, well tolerated, PDE4 inhibitor

The discovery and SAR of a new series of substituted 8-arylquinoline PDE4 inhibitors are herein described. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of emesis to efficacy in several animal models. Typical optimized compounds from this series are potent inhibitors of PDE4 (IC(50)<1nM) and also of LPS-induced TNF-alpha release in human whole blood (IC(50)<0.5microM). The same compounds are potent inhibitors of ovalbumin-induced bronchoconstriction in conscious guinea pigs (EC(50)<0.1mg/kg ip) but require a dose of about 10mg/kg po in the squirrel monkey to produce an emetic response. From this series of compounds, 23a (L-454,560) was identified as an optimized compound.     

Substituted 2-pyridinemethanol derivatives as potent and selective phosphodiesterase-4 inhibitors

The synthesis and the phosphodiesterase-4 (PDE4) inhibitory activity of 2-pyridinemethanol derivatives is described. The evaluation of the structure-activity relationship (SAR) in this series of novel PDE4 inhibitors led to the identification of compound 9 which exhibits excellent in vitro activity, desirable pharmacokinetic parameters and good efficacy in animal models of bronchoconstriction.     

Synthesis and biological evaluation of imidazol-2-one and 2-cyanoiminoimidazole derivatives: novel series of PDE4 inhibitors

This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.     

Syntheses and evaluation of pyrido[2,3-dlpyrimidine-2,4-diones as PDE 4 inhibitors

The syntheses and in vitro evaluation of a new series of pyrido[2,3-d]pyrimidine-2,4-diones bearing substituents at C-3 and/or C-4 positions on the pyridine ring are described. Some of these compounds, especially 51 and 6f, were found to be potent phosphodiesterase 4 (PDE 4) inhibitors exhibiting improved ratio of PDE 4 inhibitory activity:rolipram binding assay (RBA).     

The synthesis and biological evaluation of a novel series of phthalazine PDE4 inhibitors I

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of II compared to standards are also reported.     

Benzofuran based PDE4 inhibitors.

Replacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-methoxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzoiurans 26 is also presented.     

Discovery of a highly potent series of oxazole-based phosphodiesterase 4 inhibitors

Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.     

Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives

Synthesis and primary SAR of a novel series of 2-phenylpyrido[1,2-e]purin-4(3H)-one derivatives with piperazinyl sulfonamide substituents were described herein. As potential PDE5 inhibitors for erectile dysfunction (ED) treatment, representative compounds exhibit improved selectivity versus PDE1 and PDE6. Meanwhile, compound 3e demonstrated functional efficacy on rabbit corpus cavernosum strip in vitro.     

Phthalazine PDE4 inhibitors. Part 3: the synthesis and in vitro evaluation of derivatives with a hydrogen bond acceptor.

This communication describes the synthesis and in vitro evaluation of a novel and potent series of phthalazine phosphodiesterase type (IV) (PDE4) inhibitors. The interaction with two distinct polar binding sites allowed us to eliminate the cyclopentyloxy substitution from rolipram-like analogues.     

Design and synthesis of 4-alkynyl pyrazoles as inhibitors of PDE4: a practical access via Pd/C-Cu catalysis

The design and synthesis of 4-alkynyl pyrazole derivatives has led to the identification of new class of PDE4 inhibitors. All these compounds were accessed for the first time via a facile Pd/C-CuI-PPh(3) mediated C-C bond forming reaction between an appropriate pyrazole iodide and various terminal alkynes. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized indicated that 4-alkynyl pyrazole could be a promising template for the discovery of novel PDE4 inhibitors.     

Discovery of triazines as selective PDE4B versus PDE4D inhibitors

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive ‘closed’ conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.     

Identification of 2,3-disubstituted pyridines as potent,non-emetic PDE4 inhibitors

A series of 2,3-disubstituted pyridines were synthesized as potential non-emetic PDE4 inhibitors. To decrease brain exposure and minimize emesis, we modified the lipophilic moiety of a series of emetic PDE4 inhibitors and found that introduction of a hydroxy group into the pyridine moiety of the side chain led to non-emetic compounds with preserved PDE4 inhibitory activity. Following optimization at the phenoxy group, we identified compound 1 as a potent non-emetic PDE4 inhibitor. Compound 1 showed significant efficacy in an animal model of asthma without inducing emesis.     

Nonredundant function of phosphodiesterases 4D and 4B in neutrophil recruitment to the site of inflammation

Neutrophils have been implicated in the pathogenesis of many inflammatory lung diseases, including chronic obstructive pulmonary disease and asthma. With this study, we investigated how disruption of cAMP signaling impacts the function of neutrophil recruitment to the lung. Four genes code for type 4 phosphodiesterases (PDE4s), enzymes critical for regulation of cAMP levels and cell signaling. Ablation of two of these genes, PDE4B and PDE4D, but not PDE4A, has profound effects on neutrophil function. In a paradigm of mouse lung injury induced by endotoxin inhalation, the number of neutrophils recovered in the bronchoalveolar lavage was markedly decreased in PDE4D(-/-) and PDE4B(-/-) mice 4 and 24 h after exposure to LPS. Acute PDE4 inhibition with rolipram had additional inhibitory effects on neutrophil migration in PDE4B(-/-) and, to a lesser extent, PDE4D(-/-) mice. This decreased neutrophil recruitment occurred without major changes in chemokine accumulation in bronchoalveolar lavage, suggesting a dysfunction intrinsic to neutrophils. This hypothesis was confirmed by investigating the expression of adhesion molecules on the surface of neutrophils and chemotaxis in vitro. CD18 expression was decreased after ablation of both PDE4B and PDE4D, whereas CD11 expression was not significantly affected. Chemotaxis in response to KC and macrophage inflammatory protein-2 was markedly reduced in PDE4B(-/-) and PDE4D(-/-) neutrophils. The effect of PDE4 ablation on chemotaxis was comparable, but not additive, to the effects of acute PDE4 inhibition with rolipram. These data demonstrate that PDE4B and PDE4D play complementary, but not redundant, roles in the control of neutrophil function.     

ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions

The cAMP-specific phosphodiesterase family 4, subfamily D, isoform 3 (PDE4D3) is shown to have FQF and KIM docking sites for extracellular signal-regulated kinase 2 (ERK2) (p42(MAPK)). These straddle the target residue, Ser(579), for ERK2 phosphorylation of PDE4D3. Mutation of either or both of these docking sites prevented ERK2 from being co-immunoprecipitated with PDE4D3, ablated the ability of epidermal growth factor to inhibit PDE4D3 through ERK2 action in transfected COS cells, and attenuated the ability of ERK2 to phosphorylate PDE4D3 in vitro. The two conserved NH(2)-terminal blocks of sequence, called upstream conserved regions 1 and 2 (UCR1 and UCR2), that characterize PDE4 long isoforms, are proposed to amplify the small, inherent inhibitory effect that ERK2 phosphorylation exerts on the PDE4D catalytic unit. In contrast to this, the lone intact UCR2 region found in PDE4D1 directs COOH-terminal ERK2 phosphorylation to cause the activation of this short isoform. From the analysis of PDE4D3 truncates, it is suggested that UCR1 and UCR2 provide a regulatory signal integration module that serves to orchestrate the functional consequences of ERK2 phosphorylation. The PDE4D gene thus encodes a series of isoenzymes that are either inhibited or activated by ERK2 phosphorylation and thereby offers the potential for ERK2 activation either to increase or decrease cAMP levels in cellular compartments.     

Synthesis and biological evaluation of novel phthalazinone derivatives as topically active phosphodiesterase 4 inhibitors

Inhibitors of phosphodiesterase 4 (PDE4) are an important class of anti-inflammatory drug that act by inhibiting the production of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α). We have synthesized and evaluated a series of 2-substituted phthalazinone derivatives as PDE4 inhibitors. Structure–activity relationship studies led to the identification of benzylamine-substituted phthalazinones as potent PDE4 inhibitors that also suppressed TNF-α production by whole rat blood cells. The most potent of these, when topically administered, were effective in a mouse model of dermatitis.     

Rhodanine derivatives as novel inhibitors of PDE4

The discovery, synthesis and in vitro activity of a novel series of rhodanine based phosphodiesterase-4 (PDE4) inhibitors is described. Structure-activity relationship studies directed toward improving potency led to the development of submicromolar inhibitors 2n and 3i (IC(50)=0.89 & 0.74 microM). The replacement of rhodanine with structurally related heterocycles was also investigated and led to the synthesis of pseudothiohydantoin 7 (IC(50)=0.31 microM).