Development of Orally Bioavailable Bicyclic Pyrazolones as Inhibitors of Tumor Necrosis Factor-α Production

Abstract

2-Aryl-3-pyrimidinyl based tumor necrosis factor-alpha (TNF-alpha) inhibitors, which contain a novel bicyclic pyrazolone core, are described. Many showed low-nanomolar activity against lipopolysaccharide-induced TNF-alpha production in monocytic cells. Secondary screening data are presented for the pyrimidinyl bicyclic pyrazolones. Several of these analogues showed good oral bioavailability in rat and efficacy in the rat iodoacetate in vivo model.

Synthesis of 4,4’-(Arylmethylene)bis(1H-pyrazol-5-ols) Using Silica-bonded Ionic Liquid as Recyclable Catalyst

“…The pyrazolones and bis-pyrazolones were paid much attention for their various biological activities such as selective COX-2 inhibitory (Cho et al, 2004), antitumor (Park et al, 2005;Clark et al, 2004), cytokine inhibitors (Clark et al, 2005). Bis-pyrazolones can be used as antidepressant (Bailey et al, 1985), gastric secretion stimulatory (Rosiere & Grossman, 1951), antibacterial (Mahajan et al, 1991) and antifilarial agents (Chauhan et al, 1993).…”

Design and synthesis of coumarin substituted oxathiadiazolone derivatives having anti-inflammatory activity possibly through p38 MAP kinase inhibition

“…Numerous heterocyclic systems bearing varied functional groups have been reported to inhibit TNF-Į production through inhibition *Corresponding author. E-mail: enein@gawab.com of p38 kinase [4][5][6][7][8][9][10][11][12][13][14]. More than 234 patents on small molecules claiming to be p38 kinase inhibitors have been published since 1996 and 17 specific inhibitors are selected for further development [5].…”

“…1) are highly selective and potent inhibitiors of p38 kinase. The mode of binding of these inhibitors is also well documented [13,14]. However, the amide and ester linkages in these heterocyclic systems make them susceptible to hydrolytic cleavage due to nucleophillic attack on carbonyl carbons [15].…”

The synthesis of 4,4′-arylmethylene-bis(3-(trifluoromethyl)-1-phenyl-1H-pyrazol-5-ol) in aqueous media without catalyst

“…Nowadays, the pyrazolone derivatives were paid much attention for their various biological activities, such as antitumor [12,13], selective COX-2 inhibitory [14]. Besides, they can be used as cytokine inhibitors [15], potent catalytic activity inhibitor of human telomerase [16], therapeutics for kinase mediated inflammatory disorders [17] and dyes [18,19].…”