Design and synthesis of xanthine analogues as potent and selective PDE5 inhibitors

Wang, Yuguang; Chackalamannil, Samuel; Hu, Zhiyong; Boyle, Craig D.; Lankin, Claire M.; Yan, Xiaofeng; Xu, Ruo; Asberom, Theodros; Pissarnitski, Dmitri; Stamford, Andrew W.; Greenlee, William J.; Skell, Jeffrey; Kurowski, Stanley; Vemulapalli, Subbarao; Palamanda, Jairam; Chintala, Madhu; Myers, Joyce; Wang, Peng

doi:10.1016/s0960-894x(02)00646-7

Cited by 31 publications

(11 citation statements)

References 5 publications

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“…Wang et al [62] reported some xanthine analogs (XIV) as potent and selective PDE5 inhibitors. PDE5 is a cGMP hydrolytic enzyme which breaks down cGMP in the corpora cavernosa smooth muscles.…”

Section: Pde5-inhibiting Xanthine Analogsmentioning

confidence: 99%

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Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

Sivaprakasam¹,

Doerksen²

2009

CMC

298

147

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Topological polar surface area (TPSA), which makes use of functional group contributions based on a large database of structures, is a convenient measure of the polar surface area that avoids the need to calculate ligand 3D structure or to decide which is the relevant biological conformation or conformations. We demonstrate the utility of TPSA in 2D-QSAR for 14 sets of diverse pharmacological activity data. Even though a large pool of reports showing the importance of the classic 2D descriptors such as calculated logP (ClogP) and calculated molar refractivity (CMR) exists in the 2D-QSAR literature, this is the first report to demonstrate the value of TPSA as a relevant descriptor applicable to a large, structurally and pharmacologically diverse set of classes of compounds. We also address the limitations of applicability of this descriptor for 2D-QSAR analysis. We observed a negative correlation of TPSA with activity data for anticancer alkaloids, MT1 and MT2 agonists, MAO-B and tumor necrosis factor-alpha inhibitors and a positive correlation with inhibitory activity data for telomerase, PDE-5, GSK-3, DNA-PK, aromatase, malaria, trypanosomatids and CB2 agonists.

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Section: Pde5-inhibiting Xanthine Analogsmentioning

confidence: 99%

“…We considered 19 of the reported compounds. [62] The use of an indicator variable allowed us to consider both cyclopentyl (n=1) and cyclohexyl (n=2) sets as a single larger data set for a more effective QSAR study. (Table 13) explains 69.6% of the variance in the observed activity.…”

Section: Pde5-inhibiting Xanthine Analogsmentioning

confidence: 99%

Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

Sivaprakasam¹,

Doerksen²

2009

CMC

298

147

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“…Our investigation started with the coupling of caffeine (1) with p-bromotoluene (2 a) using copper(I) iodide as the catalyst. After screening a variety of ligands, solvents, and bases ( Table 1, entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], the best results were obtained in DMF/xylene (1:1) at 140 8C for 36 h using two equivalents of K 3 PO 4 as the base in the presence of a catalyst system that was generated in situ from CuI (20 mol %) and 1,20 mol %). An attempt to lower the amount of CuI to 10 mol % resulted in the incomplete consumption of caffeine, in spite of extended reaction time (Table 1,entry 16).…”

mentioning

confidence: 99%

“…Further removal of the benzylic group by hydrogenation should afford important biologically active C8-arylated (NH)-xanthines. [6,10] Notably, allylic theobromine could be transformed into the target compound 4 d in 86 % yield. The previous reported palladium-catalyzed methods, however, were not compatible with this substrate because of a competitive Heck reaction.…”

mentioning

confidence: 99%

Copper‐Catalyzed Direct C Arylation of Heterocycles with Aryl Bromides: Discovery of Fluorescent Core Frameworks

et al. 2009

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“…The benzylic group may also be removed by hydrogenation to afford important biologically active 8-arylated free (NH)Àxanthines. [7,12] Unlike xanthines, the coupling reactions of other N-heterocyclic substrates shown in Scheme 4 barely proceeded in the absence of carboxylic acid. To our delight, addition of pivalic acid as a cocatalyst led to significant improvement of the catalytic efficiency.…”

mentioning

confidence: 99%