The Discovery of Setileuton, a Potent and Selective 5-Lipoxygenase Inhibitor

Abstract

The discovery of novel and selective inhibitors of human 5-lipoxygenase (5-LO) is described. These compounds are potent, orally bioavailable, and active at inhibiting leukotriene biosynthesis in vivo in a dog PK/PD model. A major focus of the optimization process was to reduce affinity for the human ether-a-go-go gene potassium channel while preserving inhibitory potency on 5-LO. These efforts led to the identification of inhibitor (S)-16 (MK-0633, setileuton), a compound selected for clinical development for the treatment of respiratory diseases.

Novel Cytochrome P450-Mediated Ring Opening of the 1,3,4-Oxadiazole in Setileuton, a 5-Lipoxygenase Inhibitor

“…1) was synthesized at Merck Frosst (Kirkland, QC, Canada) as described previously (Ducharme et al, 2010). Synthetic M5 (Fig.…”

“…2) also was synthesized at Merck Frosst. Analytical amounts of M5 were prepared in a three-step synthesis starting from compound A (see supplemental material in the study by Ducharme et al, 2010). In the presence of sodium hydride and di-tert-butyl iminodicaboxylate, compound A was converted to B in a 74% isolated yield.…”

“…At the end of the incubation, two volumes of acetonitrile were added to the mixtures to terminate the reaction. A structurally similar internal standard [compound (R)-12 in the study by Ducharme et al, 2010] was added to samples when quantitation was required. Samples were centrifuged, and the supernatants were transferred into glass culture tubes and evaporated to dryness under a nitrogen stream at room temperature.…”

“…Mixtures were preincubated at 37°C for 3 min before initiating the reaction by the addition of 1 mM NADPH. After 30 min, the reaction was terminated with two volumes of acetonitrile, and a structurally similar internal standard [compound (R)-12 in the study by Ducharme et al, 2010] was added. Samples were centrifuged, and the supernatants were transferred into glass culture tubes and evaporated to dryness under a nitrogen stream.…”

Synthesis of heteryl derivatives of 2,5-disubstituted 1,3,4-okasadiazole

“…У ряду похідних, що містять 1,3,4-оксадіазол, також відомі сполуки з потуж-ним арсеналом селективної біологічної дії. Зокре-ма, на теперішній час використовуються в клініч-ній медицині: антиретровірусний агент -Raltegravir [12], протираковий агент -Zibotentan [13], транквілізуючий препарат -Fenadiazole [14], інгі-бітор 5-ліпоксигенази -MK-0633 [15], антигіпер-тензивний засіб -Nesapidil [16], антибіотик -ABT-751-oxadiazole і Furamizole [17]. Значна кіль-кість представників даного типу сполук характе-ризується вираженою бактерицидною дією на мі-кроорганізми [18], що перебувають у фазі росту.…”