Fused pyrimidine based inhibitors of phosphodiesterase 7 (PDE7): synthesis and initial structure–activity relationships

Kempson, James; Pitts, William J.; Barbosa, Joseph; Guo, Junqing; Omotoso, Omonike; Watson, Andrew J.; Stebbins, Karen; Starling, Gary C.; Dodd, John H.; Barrish, Joel C.; Felix, Raymond A.; Fischer, Karl F.

doi:10.1016/j.bmcl.2005.02.025

Cited by 36 publications

(14 citation statements)

References 11 publications

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“…PDE7 is a rolipram (PDE4 inhibitor)-insensitive, high-affinity, cAMP-specific PDE enzyme (Michaelis constant (K m ) 200 nM) with distinct kinetic properties from cAMP-dependent PDE4 isoenzymes (the K m of PDE4 is ,10-fold higher than that of PDE7). The identification of selective PDE7 inhibitors has recently been of increasing interest as they will be essential in the efforts to explain the physiological role of PDE7 [8][9][10]. Considering the reported functional role of PDE7 in T-cells [11] and the tissue localisation of its mRNA [12], targeting PDE7 may be a useful alternative in the treatment of airway diseases [6].…”

mentioning

confidence: 99%

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Chevalier¹,

Lagente²,

Dupont³

et al. 2011

European Respiratory Journal

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Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma.Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice.Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges.For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.

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mentioning

confidence: 99%

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Chevalier¹,

Lagente²,

Dupont³

et al. 2011

European Respiratory Journal

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“…In Scheme 1, the starting ethyl 2-amino-4-methylthiazole-5-carboxylate 1 [36] was warmed with acetic anhydride to produce the ethyl 2-acetamido-4-methylthiazole-5-carboxylate 2 in a good yield. When 2 was reacted with hydrazine hydrate, the 2-acetamido-4-methylthiazole-5-carboxylic acid hydrazide 3 was obtained, which was employed as the key intermediate in this part.…”

Section: Chemistrymentioning

confidence: 99%

“…Follow up of the reactions and checking the homogeneity of the compounds were made by TLC on silica gel-protected aluminum sheets (Type 60 F254, Merck, Germany) and the spots were detected by exposure to UV-lamp at k = 254. The synthesis of ethyl 2-amino-4-methylthiazole-5-carboxylate 1 was performed according to a reported literature procedure [36].…”

Section: Experimental Chemistrymentioning

confidence: 99%

Synthesis and Biological Evaluation of Some 2,4,5‐Trisubstituted Thiazole Derivatives as Potential Antimicrobial and Anticancer Agents

Al-Saadi

Faidallah

Rostom³

2008

Archiv der Pharmazie

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We report on the synthesis and biological evaluation of two series of 2,4,5-polysubstituted thiazoles comprising the acid hydrazide functionality and some derived pharmacophores known to contribute to various chemotherapeutic activities. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Of the compounds tested, 13 derivatives displayed inhibitory effect on the growth of three Gram-positive strains while they lack activity against Gram-negative bacteria. Moreover, four compounds were able to exert antifungal activity against C. albicans. Potential antibacterial and antifungal activities were linked to the thiosemicarbazide function 6a-f and those substituted with both the thioureido and thiosemicarbazide moieties 12a-f. Compounds 6f and 12f (R = 4-F-C(6)H(4)) could be considered as the most active members in this investigation with a broad spectrum of antibacterial activity against three types of Gram-positive bacteria, together with an appreciable antifungal activity against C. albicans. Compounds 6d, 6f, and 12f were twice as active as ampicillin against B. subtilis. The best antifungal activity was shown by compound 6d 50% less active than clotrimazole. 17 compounds were selected and tested for their preliminary in-vitro anticancer activity according to the current one-dose protocol of the NCI. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Compound 12f proved to be the most active anticancer member with a broad spectrum of activity against most of the tested subpanel tumor cell lines. Consequently, 12f was carried over to be tested in the five-dose assay.

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“…Many reaction parameters such as reaction temperature and time, variations in solvents, additives and catalysts or the molar ratios of the substrates can be evaluated in a few hours to optimize the desired chemistry. Owing to these facts, it is not surprising that the drug discovery and medicinal chemistry communities and many pharmaceutical companies are heavily using this high-speed technology for both lead optimization and lead generation [9][10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

“…Structural diversity in the DHPM scaffolds was generated by employing seven individual CH-acidic carbonyl compounds (10), ten different aldehydes (11) and two ureas/thioureas (12). A combination of all these building blocks would lead to a library of 140 individual DHPMs (13).…”

Section: Introductionmentioning

confidence: 99%

Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

Dallinger

Kappe

2007

Nat Protoc

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Here we report the generation of a small focused library of 12 diversely functionalized dihydropyrimidine (DHPM) derivatives via one-pot three-component Biginelli cyclocondensation of b-ketoesters, aldehydes and (thio)ureas. By applying controlled microwave heating under sealed vessel conditions using a fully automated microwave instrument including a gripper and liquid handler, the sequential synthesis of DHPMs can be performed in a shorter reaction time (10-20 min per one DHPM derivative) compared to conventional heating methods, which normally require several hours of reflux heating. The solid products either crystallize directly upon cooling or can be precipitated upon addition of water, requiring only filtration for isolation. In this way, the DHPM derivatives are obtained in high purity and no further purification by recrystallization or chromatography is necessary. This can be ascribed to the microwave heating technology where less side-product formation is often seen. The preparation of this 12-membered DHPM library can be carried out within B9 h.

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Fused pyrimidine based inhibitors of phosphodiesterase 7 (PDE7): synthesis and initial structure–activity relationships

Cited by 36 publications

References 11 publications

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma

Synthesis and Biological Evaluation of Some 2,4,5‐Trisubstituted Thiazole Derivatives as Potential Antimicrobial and Anticancer Agents

Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

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