Non-acidic pyrazole EP(1) receptor antagonists with in vivo analgesic efficacy

Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 07/2008; 18(11):3392-9. DOI: 10.1016/j.bmcl.2008.04.018
Source: PubMed


Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.

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    • "Pyrazolone derivatives form an important class of compounds having significant pharmacological activities such as anti-inflammatory, antimicrobial (Bekhit et al., 2010), analgesic (Hall et al., 2008), angiotensin antagonists (Sharma and Kohli, 2013), cytotoxic agents (Xu et al., 2013). Aryl pyrazoles are reported to have non-nucleoside HIV-I reverse transcriptase inhibitory activity (Genin et al., 2000). "
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    ABSTRACT: Inhibitors of alpha-amylase are targets for the development of novel drugs for the treatment of diabetes and obesity. Alpha amylase is an enzyme which increases the bio availability of glucose in the blood. Hence, the inhibition effects of alpha amylase of 2-[1-(4-isobutylphenyl)ethyl]-5-methyl-4-[2-(aryl-substituted)hydrazinylidene]-2,4-dihydro-3H-pyrazol-3-one (4a–l) were investigated, among them compounds 4d, 4f, 4a, and 4g have displayed good inhibitory activity. The compounds with significant results were further evaluated for their molecular modeling study using in silico method. The new series of compounds were synthesized by solvent-free microwave irradiation method and were characterized by spectral and analytical data.
    Medicinal Chemistry Research 06/2014; 23(6). DOI:10.1007/s00044-013-0846-3 · 1.40 Impact Factor
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    • "However, these studies are limited to the mouse and do not address the potential developmental impact of gene deletion. Selective ligands for the prostanoid receptors are now being reported (Naganawa et al., 2006; Hall et al., 2008; Murase et al., 2008; Maubach et al., 2009; Singh et al., 2009), which will further aid understanding of this diverse receptor family. To date, however, while many groups have used the antagonist 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH-6809) to study the EP2 receptor in combination with selective agonists and other prostanoid receptor pharmacological tools, AH-6809 is both non-selective and weakly potent (Abramovitz et al., 2000) and unsuitable for in vivo testing. "
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    ABSTRACT: Studies of the role of the prostaglandin EP(2) receptor) have been limited by the availability of potent and selective antagonist tools. Here we describe the in vitro/in vivo pharmacological characterization of a novel EP(2) receptor antagonist, PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl} azetidine-3-carboxylic acid). Functional antagonist potency was assessed in cell-based systems expressing human EP(2) receptors and native tissue preparations from human, dog and mouse. The selectivity of PF-04418948 was assessed against related receptors and a panel of GPCRs, ion channels and enzymes. The ability of PF-04418948 to pharmacologically block EP(2) receptor function in vivo was tested in rats. PF-04418948 inhibited prostaglandin E(2)(PGE(2))-induced increase in cAMP in cells expressing EP(2) receptors with a functional K(B) value of 1.8 nM. In human myometrium, PF-04418948 produced a parallel, rightward shift of the butaprost-induced inhibition of the contractions induced by electrical field stimulation with an apparent K(B) of 5.4 nM. In dog bronchiole and mouse trachea, PF-04418948 produced parallel rightward shifts of the PGE(2)-induced relaxation curve with a K(B) of 2.5 nM and an apparent K(B) of 1.3 nM respectively. Reversal of the PGE(2)-induced relaxation in the mouse trachea by PF-04418948 produced an IC(50) value of 2.7 nM. Given orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. PF-04418948 was selective for EP(2) receptors over homologous and unrelated receptors, enzymes and channels. PF-04418948 is an orally active, potent and selective surmountable EP(2) receptor antagonist that should aid further elaboration of EP(2) receptor function.
    British Journal of Pharmacology 05/2011; 164(7):1847-56. DOI:10.1111/j.1476-5381.2011.01495.x · 4.84 Impact Factor
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    ABSTRACT: In the present study, a novel series of Pyrazole derivatives (3a–m) were synthesized by condensing ethyl-3-(dimethylamino)-2-(phenylcarbonyl)prop-2-enoate with different aromatic and aliphatic hydrazines. These newly synthesized compounds were characterized by NMR, mass spectral, IR spectral studies as well as by C, H, and N analyses. All the newly synthesized compounds were screened for their antibacterial properties against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. Among the screened samples, 3c, 3f, 3k, and 3l have showed excellent antibacterial activity against all the tested bacterial strains as compared to the standard drug Ceftriaxone. Few of the compounds were found to be biologically potent. Molecular structure of compound 3i was confirmed by single crystal X-ray analysis.
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