Bioorganic & medicinal chemistry letters
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Bioorg. Med. Chem. Lett. · Dec 2009
2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.
Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.
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Fatty acid amide hydrolase (FAAH) has attracted significant attention due to its promise as an analgesic target. This has resulted in the discovery of numerous chemical classes as inhibitors of this potential therapeutic target. ⋯ Our SAR studies allowed us to optimize this series resulting in the identification of compounds 13 which were potent inhibitors of both human and rat enzyme. This series of compounds illustrated good hydrolase selectivity along with good PK properties.
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Bioorg. Med. Chem. Lett. · Oct 2009
The discovery of tertiary-amine LXR agonists with potent cholesterol efflux activity in macrophages.
The liver X receptors (LXR) play a key role in cholesterol homeostasis and lipid metabolism. SAR studies around tertiary-amine lead molecule 2, an LXR full agonist, revealed that steric and conformational changes to the acetic acid and propanolamine groups produce dramatic effects on agonist efficacy and potency. The new analogs possess good functional activity, demonstrating the ability to upregulate LXR target genes, as well as promote cholesterol efflux in macrophages.
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Bioorg. Med. Chem. Lett. · Sep 2009
Discovery of isoxazole voltage gated sodium channel blockers for treatment of chronic pain.
A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na(v)1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na(v)1.7 inhibitory activity.
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Bioorg. Med. Chem. Lett. · Aug 2009
Structure-activity relationship of etomidate derivatives at the GABA(A) receptor: Comparison with binding to 11beta-hydroxylase.
At the GABA(A) receptor, low concentrations of etomidate potentiate the inhibitory effect of GABA on specific binding of the closed channel ligand [(3)H]ethynylpropylbicycloorthobenzoate ([(3)H]EBOB). Here, we present SARs for etomidate and structurally related compounds inducing this effect. In the absence of GABA, similar SARs, but 14-20 times weaker potencies were observed. We discuss these SARs in comparison to the much higher potencies of these compounds as inhibitors of 11beta-hydroxylase.