1,4-Cyclohexanecarboxylates:  Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma

Sb, Christensen; Guider, A; Cj, Forster; Jg, Gleason; Pe, Bender; Jm, Karpinski; We, DeWolf; Ms, Barnette; Dc, Underwood; De, Griswold; Lb, Cieslinski; Burman, Miriam; Bochnowicz, Steven; Rr, Osborn; Cd, Manning; Grous, Marilyn; Lm, Hillegas; Jo, Bartus; Ryan, Martin; Ds, Eggleston; Rc, Haltiwanger; Tj, Torphy

doi:10.1021/jm970090r

Cited by 137 publications

(55 citation statements)

References 70 publications

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“…7,18 All molecules were completely inactive against PDE3. Against rolipram binding, the compounds measured were about 2-fold more potent in the rolipram binding assay than in the PDE4D enzyme assay.…”

Section: Resultsmentioning

confidence: 98%

“…Apparently, SB207499 (Ariflo; Chart 1), a PDE4 inhibitor currently in phase III clinical trials for the indications asthma and COPD, was selected based on an optimized ratio of PDE4 catalytic activity relative to affinity to the rolipram high-affinity binding site. 7 However, in clinical trials SB207499 still induced emesis at the first and/or second doses, albeit this effect apparently disappeared with continued treatment. 8 Thus, prediction of emesis in humans based on a relatively low ratio of PDE4 inhibition versus rolipram binding remains unsatisfactory.…”

Section: Introductionmentioning

confidence: 99%

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Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines: A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors

et al. 2000

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Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines: A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors

et al. 2000

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“…RS14203 (Wilhelm & Fatheree, 1994), RP73401 (Souness et al, 1995), T-440 (Kaminuma et al, 1996), R-and S-rolipram, SB207499 (Christensen et al, 1998), CDP840 (Hughes et al, 1996), CT1731 (Hughes et al, 1996), Trequinsin, L-739,010 (Hamel et al, 1997), MF-tricyclic (selective cyclo-oxygenase-2 (COX-2) inhibitor) (Oshima et al, 1996) Figure 1 shows the time course of TNF-a and PGE 2 production after LPS-stimulation of whole blood. During the incubation period, a sharp rise in TNF-a levels was observed from 2 h (2.70+0.76 ng ml 71 ) to 4 h (15.59+3.61 ng ml 71 ) and peaked at 8 h (22.92+4.77 ng ml 71 ).…”

Section: Methodsmentioning

confidence: 99%

The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B₄ in a novel human whole blood assay

Brideau

Staden

Styhler

et al. 1999

British J Pharmacology

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1 The aim of this study was to assess the inhibitory activities of phosphodiesterase type 4 (PDE4) inhibitors on tumour necrosis factor-a (TNF-a) and leukotriene B 4 (LTB 4 ) production in a novel human whole blood assay. 2 Lipopolysaccharide (LPS) stimulation of human whole blood caused a time dependent increase in TNF-a and prostaglandin E 2 (PGE 2 ) plasma levels. Inhibition of LPS-induced TNF-a by the selective PDE4 inhibitor RP73401 was proportionally enhanced with endogenous PGE 2 (maximal after 24 h). In contrast, blocking endogenous PGE 2 production with indomethacin in blood stimulated with LPS for 24 h decreased the potency of RP73401 to that observed with a 4 h LPS incubation. 3 Non-selective and selective PDE4 inhibitors showed greater inhibition of LPS-induced TNF-a after 24 h compared to 4 h. Stereoselectivity was only achieved in the 24 h method. 4 LPS-stimulation of whole blood for either 30 min or 24 h followed by N-formyl-Met-Leu-Phe (fMLP) activation resulted in low plasma LTB 4 levels. Combination of both treatments resulted in a greater than 7 fold increase in plasma LTB 4 levels. Inhibition of the double LPS and fMLP-activated LTB 4 production was observed with non-selective and PDE4-selective inhibitors. Their LTB 4 inhibitory potencies were similar to that observed in the 24 h LPS-induced TNF-a assay. Thus, stimulation of human whole blood with two LPS stimulations followed by fMLP gives rise to both TNF-a and LTB 4 and their inhibition by various compounds can be assessed in the same blood sample. 5 Calcium ionophore (A23187) stimulation of whole blood resulted in plasma LTB 4 levels similar to the double LPS and fMLP method. Inhibition of A23187-induced LTB 4 biosynthesis was also achieved by PDE4-selective inhibitors as well as the direct 5-lipoxygenase (5-LO) inhibitor L-739,010. 6 These results con®rm the anti-in¯ammatory properties of PDE4 inhibitors. Thus, this novel human whole blood can be used to assess the biochemical e cacy of PDE4 inhibitors in human subjects.

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“…The emetogenic potential of PDE4 inhibitors is suggested to correlate with their ability to displace [ [20][21][22] . We tested the activity of NIS-62949 for binding to HARBS, and the IC 50 for HARBS versus low-affinity rolipram binding site (LARBS) ratio was about 8 (calculated from table 1 ) as compared to the values for cilomilast (ϳ 0.7, table 1 ).…”

Section: Pde4 Enzyme Assaymentioning

confidence: 99%

Pharmacology of a Novel, Orally Active PDE4 Inhibitor

Dastidar¹,

Ray²,

Shirumalla³

et al. 2009

Pharmacology

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Background: Intracellular cyclic adenosine monophosphate (cAMP) in inflammatory cells and airway smooth muscle is critical to the modulation of inflammatory response generation. Phosphodiesterase 4 (PDE4), an enzyme that catalyzes cAMP degradation, is therefore being actively explored as a molecular target for the treatment of airway inflammation, particularly asthma and chronic obstructive pulmonary disease. The field has undergone major advances in optimizing generation of compounds with a safe therapeutic margin; however, most PDE4 inhibitors tested so far have unacceptable side effects, particularly nausea and vomiting. Methods: We evaluated NIS-62949 in a wide range of in vitro and ex vivo cell-based assays to ascertain its anti-inflammatory potential. The compound was evaluated in murine models of lipopolysaccharide-induced endotoxemia and pulmonary neutrophilia. Parameters of airway inflammation, airway hyperreactivity and bronchoconstriction were evaluated in a guinea pig model of antigen-induced allergy. In order to assess the emetic potential, the compound was evaluated biochemically for binding to high-affinity rolipram-binding site. Subsequently, the compound was tested in a surrogate model for emesis, and the results obtained were correlated directly to tests conducted in a Beagle dog model. Results: NIS-62949 is a potent, highly selective PDE4 inhibitor. The compound demonstrated potent ability to inhibit tumor necrosis factor-α release from human peripheral blood mononuclear cells, lymphocyte proliferation and cytokine production. The in vitro profile of NIS-62949 prompted further evaluation of the compound in vivo and the compound was found to be comparable to roflumilast in several experimental models of pulmonary inflammation. Importantly, NIS-62949 displayed a safer profile compared to roflumilast. Conclusions: Our results report the development of a promising, novel PDE4 inhibitor, NIS-62949, with a wider therapeutic window as compared to second-generation PDE4 inhibitors such as roflumilast.

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1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma

Cited by 137 publications

References 70 publications

Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines: A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors

Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines: A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors

The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B₄ in a novel human whole blood assay

Pharmacology of a Novel, Orally Active PDE4 Inhibitor

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1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma

Cited by 137 publications

References 70 publications

Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines: A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors

Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of 6,8-Disubstituted 1,7-Naphthyridines: A Novel Class of Potent and Selective Phosphodiesterase Type 4D Inhibitors

The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B4 in a novel human whole blood assay

Pharmacology of a Novel, Orally Active PDE4 Inhibitor

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The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B₄ in a novel human whole blood assay