Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic Acids as Leukotriene Biosynthesis Inhibitors

Abstract

A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB(4) biosynthesis in the intact human neutrophil with IC(50) of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED(50) = 0.14 mg/kg) and rat anaphylaxis model (ED(50) = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE(4) biosynthesis (ED(50) of 0.1 mg/kg) and eosinophil influx (ED(50) of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.

2,6‐Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure–Activity Relationships

“…The 2‐substituted quinoxaline 16 was accomplished from 1,2‐diamino benzene and 1,3‐hydroxypropan‐2‐one through a one‐pot process using palladium acetate‐catalyzed aerobic oxidation, followed by in situ trapping, as reported previously, to yield 67 . Consequent conversion into the corresponding chloro derivative 68 , using trichloroisocyanuric acid, and reaction with 2,6‐difluoro‐3‐hydroxybenzamide afforded 16 .…”

RBx 7796: A novel inhibitor of 5-lipoxygenase

“…Synthetic inhibitors of 5-lipoxygenase enzyme have shown protective effect in experimental animal models of airway infl ammation and in human bronchial asthma [17][18][19][20][21][22]. Although, considerable effort has been made to design an effective inhibitor of 5-lipoxygenase, at the present time the most successful chemotype belongs to N-hydroxyurea category [16,[23][24][25][26]. This chemotype reportedly suffers from poor bioavailability; inhibitor specifi city and safety issues like hepatic and renal abnormality, myelosuppression, mild gastrointestinal abnormality etc [26][27].…”

Synthesis and <i>in Vivo</i> Evaluation of Novel Quinoline Derivatives as Phosphodiesterase 10A Inhibitors

“…Treatment of 30 with aqueous sodium hydroxide solution and subsequent DMF-DMA followed by the addition of methylhydrazine yielded amino pyrazole analogue 31, which after reductive alkylation with 4-(quinolin-2-yl)-benzaldehyde gave compound 32. 27) Further reductive alkylation with formaldehyde afforded compound 33.…”