Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK).

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.

Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK).

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.

Total synthesis of 7,11-cyclobotryococca-5,12,26-triene using an oxidative radical cyclization as a key step.

An efficient total synthesis of the novel botryococcene-related hydrocarbon 7,11-cyclobotryococca-5,12,26-triene is reported that uses, as a key step, an oxidative radical cyclization of a 4-pentenyl malonate for the synthesis of a [3.3.0]-bicyclic gamma-lactone.

5-HT(1A) activation counteracts cardiovascular but not hypophagic effects of sibutramine in rats.

The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5-hydroxytryptamine (5-HT(1A)) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1-10 mg/kg p.o.) dose-dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5-HT(1A) agonist F-11440 (2.5 mg/kg p.o.) attenuated sibutramine-induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F-11440. These results suggest that sibutramine-induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5-HT(1A) activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5-HT(1A) activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5-HT(1A) activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5-HT(1A) activation combined with NA transporter blockade.

Looking glass inhibitors: efficient synthesis and biological evaluation of D-deoxyfuconojirimycin.

1,6-Dideoxygalactostatin, the mirror image of 1-deoxy-L-fuconojirimycin, was efficiently prepared from 2,3-O-isopropylidene-L-lyxonolactone in four steps and evaluated as a glycosidase inhibitor.