安全局部治疗青光眼的倍他洛尔眼部特异性化学输送系统。

Drug design and discovery Pub Date : 1997-08-01
H H Farag, W M Wu, M D Barros, G Somogyi, L Prokai, N Bodor
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引用次数: 0

摘要

通过氧化倍他洛尔,然后用适当的氧化胺淬灭酮,制备了新型的酮甲氧肟(BMO)和倍他洛尔(B)的肟(BO)类似物。Z同分异构体在动力学上更有利,在热力学上更稳定。在缓冲液中观察到所有纯异构体达到Z/E平衡混合物的异构化。然而,在生物液体中,平衡要快得多。任何一种肟衍生物的眼部给药,都能将倍他洛尔特异性地递送到眼部组织,在虹膜睫状体中浓度最高。BMO和BO均可显著降低正常血压家兔的眼压。即使静脉给药,对兔和大鼠异丙肾上腺素诱导的心动过速也没有影响。观察到非常轻微的眼睛刺激,比盐酸倍他洛尔的刺激要小,特别是马来酸BMO,它是安全治疗青光眼的极好候选药物。
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Ocular-specific chemical delivery systems of betaxolol for safe local treatment of glaucoma.

Novel ketomethoxime (BMO) and oxime (BO) analogs of betaxolol (B) were prepared through the oxidation of betaxolol, followed by quenching of the ketone with the appropriate oxyamine. The Z isomers were kinetically favored and thermodynamically more stable. Isomerization to reach an equilibrium mixture of Z/E was observed for all pure isomers in buffers. Equilibration is much faster, however in biological fluids. Ocular administration of any of the oxime derivatives, delivers betaxolol specifically to the eye tissues, with the highest concentration in the iris ciliary body. Both BMO and BO, when applied topically, showed marked reduction of intraocular pressure (IOP) in normotensive rabbits. No effect on isoproterenol-induced tachycardia in rabbits and rats were observed, even after iv. administration. Very mild eye irritation, which was less than that of betaxolol hydrochloride, was observed particularly with BMO maleate, which is an excellent candidate for safe treatment of glaucoma.

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