[reaction: see text] The marine sponge derived beta2-adrenoceptor agonist S1319 has been synthesized following a six-step linear sequence. Central to the approach employed is the formation of a 7-lithiated-2,4-dialkoxybenzothiazole intermediate obtained via a directed-lithiation/benzyne-mediated cyclization reaction. The incorporation of a tert-butyl ether residue into the cyclization precursor for the pivotal ring-closing step has been shown to significantly increase the efficiency of the reaction by the suppression of a competing directed ortho-lithiation reaction.

01 Feb 2000·Inflammation ResearchQ3 · MEDICINE

The effects of S1319, a novel marine sponge-derived β 2 -adrenoceptor agonist, on IgE-mediated activation of human cultured mast cells

Q3 · MEDICINE

Article

Author: Ueno, A. ; Shindo, K. ; Takei, M. ; Suzuki, H. ; Higa, T. ; Fukamachi, H.

OBJECTIVEThis study aimed to evaluate the ability of S1319 (4-hydroxy-7-[1-(1-hydroxy-2-methylamino) ethyl]-1,3-benzothiazol-2(3H)-one acetate), a novel beta2-adrenoceptor selective agonist derived from marine sponge, to inhibit IgE-mediated activation of human cultured mast cells (HCMC) in vitro.MATERIALS AND METHODSWe examined the effect of S1319 (racemate) on tryptase release and tumor necrosis factor-alpha (TNF-alpha) production in HCMC generated from human cord blood cells, after cross-linking of high affinity immunoglobulin E receptors (FcepsilonRI), compared with those of the nonselective beta-adrenoceptor agonist, isoproterenol (R-isomer), the selective beta2-adrenoceptor agonist, salbutamol (racemate), and the selective and long-acting beta2-adrenoceptor agonist, formoterol (racemate). We also evaluated the effect of S1319 on the intracellular cAMP level, inositol phosphate production and protein tyrosine phosphorylation in HCMC.RESULTSS1319 and beta-adrenoceptor agonists inhibited the IgE-mediated release of tryptase. Approximate IC50 values of S1319, formoterol, isoproterenol and albuterol for the inhibition of tryptase release were 0.51+/-0.12, 0.15+/-0.1, 0.80+/-0.09, and 28+/-32.4 nM, respectively. S1319 and beta-adrenoceptor agonists also inhibited TNF-alpha production by HCMC in a concentration-dependent manner. Approximate IC50 values of S1319, formoterol and isoproterenol for the inhibition of TNF-alpha production were 0.19+/-0.03, 0.28+/-0.02 and 0.32+/-0.03 nM, respectively. S1319 caused a concentration-dependent increase in total cell cyclic AMP levels in HCMC. On the other hand, S1319 inhibited the accumulation of inositol 1,4,5-triphosphate and IgE-mediated protein tyrosine phosphorylation of 42-kDa protein, p42 mitogen activated protein (MAP) kinase (ERK-2).CONCLUSIONThese results indicate that S 1319 and beta-adrenoceptor agonists are potent inhibitors of the IgE-mediated release of mediators from HCMC.

01 Oct 1999·British Journal of PharmacologyQ2 · MEDICINE

Tracheal relaxing effects and β₂ adrenoceptor selectivity of S1319, a novel sponge‐derived bronchodilator agent, in isolated guinea‐pig tissues

Q2 · MEDICINE

Article

Author: Fukamachi, Hiromi ; Sakakibara, Masayuki ; Takei, Masao ; Sindo, Kazutoshi ; Ueno, Akihiro ; Miura, Toru ; Higa, Tatsuo ; Suzuki, Hidefumi

S1319 (4‐hydroxy‐7‐[1‐(1‐hydroxy‐2‐methylamino)ethyl]‐1,3‐benzothiazol‐2(3H)‐one acetate), a novel non‐catecholamine β‐adrenoceptor agonist, has been compared with isoprenaline, salbutamol and formoterol for activity in vitro on a range of β‐adrenoceptor containing preparations from guinea‐pig.

S1319, like isoprenaline, salbutamol and formoterol, relaxed preparations of guinea‐pig trachea (contracted by histamine) in a concentration‐dependent manner. The relaxing activity of S1319 appeared to be more potent than that of isoprenaline and salbutamol, and similar to that of formoterol (pD2 values of 10.58±0.03 vs 7.60±0.01, 7.50±0.01 and 10.52±0.04, respectively), and was blocked by the β2‐adrenoceptor selective antagonist (ICI 118,551). The intrinsic activity of S1319 was close to 1.0.

In the β1‐adrenoceptor containing preparations, guinea‐pig right and left atria, a monophasic inotropic response of S1319 was observed. The pD2 value of S1319 for left atrial and right atrial inotropism was 6.70±0.15 and 7.81±0.01, respectively.

The selectivity ratio (trachea/left atrial inotropism) of S1319, formoterol, salbutamol and isoprenaline was 8523, 284, 4.8 and 0.45, respectively. The relative selectivity ratio of S1319 was 18743, 1858 and 30 times greater than that of isoprenaline, salbutamol and formoterol, respectively.

Relaxant responses of guinea‐pig trachea to S1319 declined rapidly when the agonist was washed from the tissues, with complete recovery within 30 min. The duration of action of S1319 was similar to that of isoprenaline and less than that of salbutamol and formoterol.

In summary, S1319, a sponge‐derived β‐adrenoceptor agonist, is a potent and selective β2‐adrenoceptor agonist with a short‐duration of action in isolated guinea‐pig tracheas.

British Journal of Pharmacology (1999) 128, 716–720; doi:10.1038/sj.bjp.0702839

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Indication	Highest Phase	Country/Location	Organization	Date
Respiration Disorders	Discovery	JP	Kirin Brewery Co. Ltd.	-

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