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Abstract: Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors. [Copyright &y& Elsevier]

Abstract: The discovery and SAR of a novel series of substituted 2,2-bisaryl-bicycloheptane inhibitors of 5-lipoxygenase activating protein (FLAP) are herein described. SAR studies have shown that 2,5-substitution on the exo-aryl group is optimal for potency. The most potent compounds in this series have an ortho-nitrogen aryl linked with a methyleneoxy as the 5-substituent and a polar group such as a urethane as the 2-substituent. One of the most potent compounds identified is the 5-benzothiazolymethoxy-2-pyridinylcarbamate derivative 2 (FLAP IC50 =2.8nM) which blocks 89% of ragweed induced urinary LTE4 production in dogs (at an I.V. dose of 2.5μg/kg/min). This compound inhibits calcium ionophore stimulated LTB4 production in both human polymorphonuclear (PMN) leukocytes and human whole blood (IC50 =2.0 and 33nM, respectively). [Copyright &y& Elsevier]

Abstract: We report the development of the novel N-substituted benzimidazole 11 as a potent and selective human formyl peptide receptor-like 1 (hFPRL1) agonist. This compound and its less active enantiomer 12 were identified as useful tools for studying receptor function in vitro. [Copyright &y& Elsevier]

Abstract: We report the discovery of potent agonists for the human formyl-peptide-like 1 receptor (hFPRL1). These compounds did not act at a closely related receptor denoted human formyl peptide receptor (hFPR) up to 10μM concentration. Recent studies have indicated that agonizing this receptor may promote resolution of inflammation. In an exploratory study, a novel hFPRL1 agonist showed efficacy in a mouse ear inflammation model following oral administration. [Copyright &y& Elsevier]

Abstract: Leukotriene biosynthesis inhibitors have potential as therapeutic agents for asthma and inflammatory diseases. A novel series of substituted coumarin derivatives has been synthesized and the structure–activity relationship was evaluated with respect to their ability to inhibit the formation of leukotrienes via the human 5-lipoxygenase enzyme. [Copyright &y& Elsevier]

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays. [Copyright &y& Elsevier]