Synthesis and Biological Evaluation of 1,2,4-Triazinylphenylalkylthiazolecarboxylic Acid Esters as Cytokine-Inhibiting Antedrugs with Strong Bronchodilating Effects in an Animal Model of Asthma

Abstract

The influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma. We describe here the synthesis and pharmacological evaluation of a series of triazinylphenylalkylthiazolecarboxylic acid esters that were designed to act as lung-specific antedrugs and inhibitors of the production of interleukin (IL)-5, a primary eosinophil-activating and proinflammatory cytokine. Closer examination of the hydroxypropyl ester, 15, indicated its high metabolic stability (t(1/2) > 240 min) in human lung S9 fraction but rapid conversion (t(1/2) = 15 min) into the pharmacologically inactive carboxylic acid by human liver preparations. In stimulated human whole blood cultures, 15 reduced not only the production of IL-5 (IC(50) = 78 nM) but also the biosynthesis of the monocyte chemotactic proteins MCP-1 (IC(50) = 220 nM), MCP-2 (IC(50) = 580 nM), and MCP-3 (IC(50) = 80 nM). In vivo, intratracheal administration of 15 (6 mg/animal) to allergic sheep, either before (-4 h) or after (+1.5 h) the pulmonary allergen challenge, completely abrogated the late-phase airway response and reduced the bronchial hyperreactivity to inhaled carbachol.

Improved 2,4‐Diarylthiazole‐Based Antiprion Agents: Switching the Sense of the Amide Group at C5 Leads to an Increase in Potency

“…Variation at the 2-position of the thiazole ring was then explored, whilst maintaining the best substituents at C5 identified above, in an attempt to improve activity. Hantzsch thiazole synthesis [12] from ethyl 2-benzoyl-2-bromoacetate 3 [13] and a range of thioamides provided 4-phenylthiazole-5-carboxylic esters 4 a-c, which, following aminolysis mediated by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), [14] afforded a range of new test compounds, 5 a-c and 6 a-c (Scheme 2), analogous to the existing lead compounds 2 i and 2 m.…”

“…Ethyl 2-bromo-2-benzoylacetate (3): [13] A solution of ethyl benzoylacetate (6.93 mL, 7.69 g, 40 mmol) in CH 2 Cl 2 (180 mL) was cooled to 0 8C, then bromine (1.84 mL, 5.75 g, 36 mmol) in the same solvent (30 mL) was added dropwise over 15 min. The reaction mixture was stirred for an additional 1 h then transferred to a separating funnel, washed with 10 % K 2 CO 3 (150 mL), dried over MgSO 4 and evaporated giving a thick oily residue.…”

p38 Mitogen activated protein kinase (MAPK): a new therapeutic target for reducing the risk of adverse pregnancy outcomes

“…This procedure, however, continues to be actively developed for steroidal anti-inflammatory antedrug treatment for bronchial asthma [122], and in developing cytokine-inhibiting antedrugs for treatment of asthma [123,124]. For example, steroid acid esters with intact structures of potent glucocorticoids retain the ante-inflammatory activity of the parent compound but upon entry into the systemic circulation are hydrolyzed to form inactive readily excreteable steroid acids[125].…”

“…The severity of allergic asthma is associated with the influx of leukocytes (eosinophils, lymphocytes and monocytes) and their production of proinflammatory cytokines has encouraged the design of cytokine-inhibiting antedrugs with strong broncho-dilating effects in an animal model of asthma [123]. The triazinylphenylalkylthiazolecarboxylic acid esters are a group of pharmaceuticals designed to act as lung-specific antedrugs and inhibitors of the production of IL-5, a primary eosinophil-activating and proinflammatory cytokine.…”

Retrometabolism‐Based Drug Design and Targeting

“…The corresponding carboxylic ester incorporating compound, MLD987 (145) (Fig. 33) [355]. Since the influx of leukocytes (eosinophils, lymphocytes, and monocytes) into the airways and their production of proinflammatory cytokines contribute to the severity of allergic asthma, a localized cytokine inhibitor is of considerable therapeutic interest, and inhaled SDs could provide the needed lung-specificity.…”