Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents.

Preclinical and clinical studies of phosphodiesterase 4 inhibitors have shown that these agents may find utility in a wide range of inflammatory disorders, including asthma, chronic obstructive pulmonary disease, atopic dermatitis, rheumatoid arthritis, multiple sclerosis and various neurological disorders. The future of this class of drugs will depend upon the ability to demonstrate a reasonable safety margin against emesis and other typical phosphodieserase (PDE4) side effects, as well as in identification of the inflammatory disorder(s) most relevant to PDE4 inhibition.     

Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.     

Phosphodiesterase inhibitors. Part 4: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.     

Phosphodiesterase inhibitors. Part 2: Design, synthesis, and structure-activity relationships of dual PDE3/4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory and bronchodilatory activity

A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (−)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.     

Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration

Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-α from isolated human peripheral blood mononuclear cells with a pIC₅₀ of 11.1. GSK256066 also has a suitable profile for inhaled dosing.     

Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation

To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[¹¹C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([¹¹C]1) and N-(4-[¹¹C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([¹¹C]MPPA, [¹¹C]4) were prepared from their corresponding precursors 2 and 5 with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A_M) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.     

Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast

Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7′ in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3′-centre to C-4′ strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.     

Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template

Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100 mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.     

Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett. 2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.     

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

Phosphodiesterases (PDEs) are responsible for the breakdown of intracellular cyclic nucleotides, from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells. This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases. For example, cigarette smoke-induced neutrophilia in BAL was dose and time dependently reduced by cilomilast. Beside the undesired side effects associated with the first generation of PDE4 inhibitors, the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstructive pulmonary diseases trials, thus re-enhancing the interest on these classes of compounds. However, the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored. We demonstrated that selective PDE4 inhibitor RP 73-401 reduced matrix metalloproteinase (MMP)-9 activity and TGF-beta1 release during LPS-induced lung injury in mice and that CI-1044 inhibited the production of MMP-1 and MMP-2 from human lung fibroblasts stimulated by pro-inflammatory cytokines. Since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure, our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases.     

Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).     

8-Methoxyquinoline-5-carboxamides as PDE4 inhibitors: a potential treatment for asthma

A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).     

Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction

In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.     

Exploration of the 5-bromopyrimidin-4(3H)-ones as potent inhibitors of PDE5

The substituents both at the 6-position of the 5-bromopyrimidinone ring and at the 5′-position of the phenyl ring of 5-bromopyrimidin-4(3H)-ones were explored. 5-Bromo-6-isopropyl-2-(2-propoxy-phenyl)pyrimidin-4(3H)-one was identified as a new scaffold for potent PDE5 inhibitors. The crystal structures of PDE5/2e and PDE5/10a complexes provided a structural basis for the inhibition of 5-bromopyrimidinones to PDE5. In addition, it was also found that there is a great tolerance for the substitution at the 5′-position of the phenyl ring of 5-bormopyrimidinones and the resulted compound 13a has the highest inhibition activity to PDE5 (IC₅₀, 1.7 nM).     

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs

Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this Letter we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.     

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs

In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.     

Quinolines as a novel structural class of potent and selective PDE4 inhibitors: Optimisation for oral administration

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD     

Phosphodiesterase 4 inhibitors as airways smooth muscle relaxant agents: synthesis and biological activities of triazine derivatives

A series of triazine derivatives was synthesized. The compounds were evaluated for tracheal smooth muscle relaxant and type 4 phosphodiesterase inhibitory activities. A highly significant correlation was observed between the two effects. Two compounds exhibited potent relaxant activity (EC50: 17 and 24 nM) and might be useful for the treatment of asthma.     

1,1-Diarylalkenes as anticancer agents: dual inhibitors of tubulin polymerization and phosphodiesterase 4

A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ～1 μM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds' solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20 mg/kg qd.     

7-Methoxybenzofuran-4-carboxamides as PDE 4 inhibitors: a potential treatment for asthma

The synthesis and pharmacological profile of a novel series of 7-methoxybenzofuran-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).