Carboxy-Substituted Cinnamides:  A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

Abstract

A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B4 (LTB4) receptor. Binding was determined through measurement of [3H]LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.

Peroxisomes in Dermatology. Part II

“…61 All these mechanisms lead to a complex modulation and tissue specificity of the peroxisomal activation by different COX inhibitors as well as by new drugs modulating lipoxygenase pathways. 62,63 PPAR modulation may be helpful in moderating the central fat distribution seen with increased corticosteroids and in HIV-1 patients who are often are on HIV-1 protease inhibitors. 54,55 Under these conditions, a decrease in the PPAR␣-to-PPAR␥ ratio and an imbalance in PPAR␥1-to-PPAR␥2 mRNA production and/or activation appear to be important.…”

Peroxisomes in Dermatology. Part II

“…38,6o In addition, nonspecific COX inhibitors increase production of bioactive lipids through the lipoxygenase pathways (the COX2specific inhibitors do not); some of these lipoxygenase products can lead to PPAR activation/" All these mechanisms lead to a complex modulation and tissue specificity of the peroxisomal activation by different COX inhibitors as well as by new drugs modulating lipoxygenase pathways. 62,63 PPAR modulation may be helpful in moderating the central fat distribution seen with increased corticosteroids and in HIV-l patients who are often are on HIV-l protease inhibitors. 54,55 Under these conditions, a decrease in the PPARex-to-PPAR" ratio and an imbalance in PPAR,,1-to-PPAR,,2 mRNA production and/or activation appear to be important.…”

Asymmetric Synthesis of Neolignans (−)-epi-Conocarpan and (+)-Conocarpan via Rh(II)-Catalyzed C−H Insertion Process and Revision of the Absolute Configuration of (−)-epi-Conocarpan

“…5-Bromoaryldiazoacetate 9a was prepared as shown in Scheme . O -Alkylation of methyl (5-bromo-2-hydroxyphenyl)acetate ( 11 ) with 4-(triisopropylsilyloxy)benzyl bromide ( 12 ) provided 5-bromoarylacetate 13 in 68% yield. Since attempted direct diazo transfer to 13 with p -acetamidebenzenesulfonyl azide and DBU in CH 3 CN gave decomposition products, we used the Danheiser modification of Regitz’s diazo transfer reaction .…”