Diffusion, partitioning, and binding of two aldose-reductase inhibitors (ARI) in the rat lens were investigated under in vitro conditions. A lipophilic ARI (CT-112) and a hydrophilic ARI (AD-5467) were used as model drugs. Under lens-uptake conditions, the drug concentration in the lens increased rapidly during the initial 10 hr and reached steady state (equilibrium) after 24 hr. Despite the equilibrium concentration of CT-112 in the lens which is approximately three times of that of AD-5467, the inhibition rate of CT-112 against the accumulation of sugar alcohols was appreciably lower than that for AD-5467. The equilibrium concentration in the lens after the penetration/binding experiment also suggested that AD-5467 may interact with the target sites of enzymes more than that for CT-112. The time course of the lens concentration during the uptake and desorption experiments was well described by a diffusion/binding model assuming a Langmuir binding. The diffusion coefficient, the partition coefficient, and binding parameters in the rat lens were determined for the two ARIs.

01 Jan 1990·Current Eye ResearchQ4 · MEDICINE

In vitrostudy of aldose reductase inhibitor concentrations in the lens and inhibitory effect on sugar alcohol accumulation

Q4 · MEDICINE

Article

Author: Yujiro Yamamoto ; Akira Ohtori

Rat lenses were cultured in a medium containing either 30mM xylose or 30mM glucose. Inhibitory effects of two aldose reductase inhibitors, AD-5467 and CT-112, on the accumulation of sugar alcohols and the concentrations of the drugs in the lens were measured. Inhibitory effect of lens opacification by the drugs were also observed. Lens opacification was apparently inhibited in a medium containing each of the drugs. Inhibition rates for sugar alcohol accumulation by AD-5467 and CT-112 were unrelated to the kinds of added sugars. 50% inhibition-concentration in the medium was 0.82-1.02 x 10(-7) M for AD-5467 and 3.78-5.92 x 10(-7) M for CT-112, and the resulting concentration of drug in the lens was 2.33-3.08 nmole/g lens for AD-5467 vs. 21.19-24.63 nmole/g lens for CT-112. The results above indicated that the concentration of CT-112 should be 4.6-5.8 times of that of AD-5467 in the medium to attain the same inhibitory effect on sugar alcohol accumulation, and 8.0-9.1 times more CT-112 is needed in the lens. A linear correlation was found on a bilogarithmic graph of concentrations in the medium and in the lens for both drugs. This correlation is an empirical adsorption isotherm shown by Freundrich. So this suggested that both drugs were adsorbed into the lens. The rate of adsorption varied with the drugs. Even when the drug concentrations in the medium were the same, the concentration of CT-112 in the lens was 2-4 times higher than that of AD-5467.(ABSTRACT TRUNCATED AT 250 WORDS)

01 Jan 1990·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: Synthesis and biological activity.

Q4 · MEDICINE

Article

Author: Tawada, Hiroyuki ; Yamamoto, Yujiro ; Sugiyama, Yasuo ; Ikeda, Hitoshi ; Meguro, Kanji

N-Acetic acid derivatives (I) of 2-substituted 1,4-benzoxazines and benzothiazines were designed and synthesized for evaluation as new aldose reductase inhibitors. In general, 3-thioxo derivatives were more potent inhibitors of aldose reductase from human palcenta in vitro than the corresponding 3-oxo derivatives. While many compounds (I) were not very effective in inhibiting sorbitol accumulation in the rat sciatic nerve in vivo, the 3-thioxo compounds bearing an isopropyl group at the 2-position showed highly potent activity in the in vivo assay. Compound 46 (AD-5467) was selected from this series as a candidate for further development.

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Indication	Highest Phase	Country/Location	Organization	Date
Cataract	Phase 2	-	Takeda Pharmaceutical Co., Ltd.	-
Cataract	Phase 2	-	Senju Pharmaceutical Co., Ltd.	-
Diabetes Complications	Phase 2	JP	-	-
Diabetic Retinopathy	Phase 2	-	Takeda Pharmaceutical Co., Ltd.	-
Diabetic Retinopathy	Phase 2	-	Senju Pharmaceutical Co., Ltd.	-

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