5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods

This work was supported by the Foundation for Science and Technology (FCT), Portugal (projects PTDC/QUI-QUI/113687/2009 and PEst-C/QUI/UI0081/2013). A.G. (SFRH/BD/43531/2008) and M.J.M. (SFRH/BD/61262/2009) thank FCT for grants.

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Chromone: A Valid Scaffold in Medicinal Chemistry

Adipose tissue regulates numerous physiological processes, and its dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance and type 2 diabetes mellitus (T2DM). Although several US-approved treatments for obesity and T2DM exist, these are limited by adverse effects and a lack of effective long-term glucose control. In this Review, we provide an overview of the role of adipose tissue in metabolic homeostasis and assess emerging novel therapeutic strategies targeting adipose tissue, including adipokine-based strategies, promotion of white adipose tissue beiging as well as reduction of inflammation and fibrosis.

Targeting adipose tissue in the treatment of obesity-associated diabetes

Gallic acid inhibits histamine release and pro-inflammatory cytokine production in mast cells.

Alan Saltiel and his colleagues report that the approved drug amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.

An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice

A number of 3-(1H-tetrazol-5-yl)chromones were synthesized and found to have antiallergic activity in the rat passive cutaneous anaphylaxis (PCA) test. These compounds are active when administered orally in rats and of possible value for the treatment of asthma.

Studies on antianaphylactic agents. 5. Synthesis of 3-(1H-tetrazol-5-yl)chromones, a new series of antiallergic substances.

Pharmacological profile of AA-861, a 5-lipoxygenase inhibitor.

Amlexanox markedly inhibits histamine release from rat mast cells. To clarify the mechanism of this inhibition, we investigated the effect of amlexanox on cAMP content, which, when increased, inhibits histamine release in rat peritoneal mast cells. At concentrations of 10––8––10––6M, amlexanox or isoproterenol increased the cAMP content of mast cells over that of control cells about 2-fold. When the mast cells were incubated with 10––8, 10––7 and 10––6M of amlexanox combined with 10––7M isoproterenol, the cAMP contents were synergistically increased 15-, 60- and 88-fold, respectively. 3-Isobutyl-1-methylxanthine (IBMX) at 10––6––10––4M increased the cAMP content 1.7––3.8-fold, and a combination of 10––4M IBMX and 10––7M isoproterenol synergistically increased the cAMP content 41-fold. A combination of amlexanox and IBMX synergistically increased the cAMP content 19-fold. The increase in cAMP content, when amlexanox and isoproterenol were combined, was transient; it peaked at 0.5 min after the drugs were administered, then decreased to 20–30% of the peak value about 2 min later. Pretreatment of mast cells with amlexanox reduced the effect of the combination of amlexanox and isoproterenol, indicating tachyphylaxis; pretreatment with IBMX had no such effect. The cAMP content of macrophages was also increased by amlexanox, but when combined with isoproterenol or PGE2, the effect was additive. Amlexanox inhibited cAMP phosphodiesterase in rat mast cells; its IC50 value was 1.4 × 10––5M, and its inhibitory activity was half that of IBMX. These results suggest that amlexanox inhibits histamine release by augmenting the cAMP content in mast cells, and that this augmentation is caused by enhancing the cAMP generation and, additively, by inhibiting cAMP phosphodiesterase.

Mechanism of action of an antiallergic agent, amlexanox (AA-673), in inhibiting histamine release from mast cells. Acceleration of cAMP generation and inhibition of phosphodiesterase.

Disclosed is a compound represented by the formula (I) or a salt thereof: wherein R1 represents an aliphatic hydrocarbon, aralkyl or aryl group which may be substituted; R2 represents hydrogen, an aliphatic hydrocarbon group having one or more substituents, an aryl group which may be substituted, an amino group which may be substituted, a formyl group; a nitro group or a halogeno group; A represents a divalent hydrocarbon chain of 2 to 4 carbon atoms which may be substituted; and m represents an integer of 0 to 2, which is useful for treatment and prevention of diseases induced by abnormalities in regulation of reactions in vivo mediated through endothelin or interleukin 1, and of immune diseases and inflammatory diseases.

Sulfur-containing fused pyrimidine derivatives, their production and use

The syntheses of trans-3-(4-oxo-4H-1-benzypyran-3)acrylic acid and a number of analogs shown to be highly active in antiallergic bioassays are described. These compounds are of possible value in the treatment of asthma. The structural requirements for biological activity are discussed with reference to the type of the substituents on the chromone ring or positions of linkage of the acrylic acid on the pyrone ring.

Studies on antianaphylactic agents. 4. Synthesis and structure-activity relationships of 3-(4-oxo-4H-1-benzopyran-3)acrylic acids, a new series of antiallergic substances, and some related compounds

Taketoshi Saijo

Papers

Studies on antianaphylactic agents. 5. Synthesis of 3-(1H-tetrazol-5-yl)chromones, a new series of antiallergic substances.

Pharmacological profile of AA-861, a 5-lipoxygenase inhibitor.

Mechanism of action of an antiallergic agent, amlexanox (AA-673), in inhibiting histamine release from mast cells. Acceleration of cAMP generation and inhibition of phosphodiesterase.

Sulfur-containing fused pyrimidine derivatives, their production and use

Studies on antianaphylactic agents. 4. Synthesis and structure-activity relationships of 3-(4-oxo-4H-1-benzopyran-3)acrylic acids, a new series of antiallergic substances, and some related compounds