Novel, potent aldose reductase inhibitors: 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid (zopolrestat) and congeners

Abstract

A new working hypothesis that there is a hitherto unrecognized binding site on the aldose reductase (AR) enzyme with strong affinity for benzothiazoles was pursued for the design of novel, potent aldose reductase inhibitors (ARIs). The first application of this hypothesis led to a novel series of 3,4-dihydro-4-oxo-3-(benzothiazolylmethyl)-1-phthalazineacetic+ + + acids. The parent of this series (207) was a potent inhibitor of AR from human placenta (IC50 = 1.9 x 10(-8) M) and was orally active in preventing sorbitol accumulation in rat sciatic nerve, in an acute test of diabetic complications (ED50 = 18.5 mg/kg). Optimization of this lead through medicinal chemical rationale, including analogy from other drug series, led to more potent congeners of 207 and culminated in the design of 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (216, CP-73,850, zopolrestat). Zopolrestat was found to be more potent than 207, both in vitro and in vivo. Its IC50 against AR and ED50 in the acute test were 3.1 x 10(-9)M and 3.6 mg/kg, respectively. Its ED50s in reversing already elevated sorbitol accumulation in rat sciatic nerve, retina, and lens in a chronic test were 1.9, 17.6, and 18.4 mg/kg, respectively. It was well absorbed in diabetic patients, resulting in high blood level, showed a highly favorable plasma half-life (27.5 h), and is undergoing further clinical evaluation. An assortment of synthetic methods used for the construction of benzothiazoles, including an efficient synthesis of zopolrestat, is described. Structure-activity relationships in the new series are discussed.

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…Epalrestat was developed in 1983 [49] and has been marketed in Japan, and recently in China and India. Tolrestat, a strong ARI and potential drug for the treatment of diabetic complications [50], was approved to several markets, but withdrawn for the reason of risk of severe liver toxicity and death.The typical carboxylic acid ARIs also include zenarestat [51], zopolrestat [52], and ponalrestat [53]. Zenarestat is a potential drug for the treatment of diabetic neuropathy, retinopathy and cataracts.…”

Recent Advances in Biomimetic Synthesis Involving Cyclodextrins

“…For example the thiazole in vitamin B serves as an electron sink, and its coenzyme form is important for the decarboxylation of -keto acids and is present in various natural products and herbicides. This important and useful structural motif has found application in drug development, as these exhibit diverse biological activities such as anti-glutamate, anti-Parkinson (Benazzouz et al, 1995), anti-microbial (Palmer et al, 1971), anthelmintic, anti-inflammatory (Haviv et al, 1988), anti-hyperlipidemic, anti-hypertension (Patt et al, 1992), and anti-oxidant properties as well as inhibition of enzymes such as acetylcholine esterase (Nagel et al, 1995), aldose reductase (Mylari et al, 1991), lipoxygenase (Hadjipavlou-Litina & Geronikaki,1998), ATPase (Sohn et al, 1999), and HCV helicase (phoon et al, 2001). Aminothiazoles are reported as a new class of adenosine receptor antagonists and ligands of estrogen receptors.…”

Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

“…Tolrestat (1), which was launched in 1989, was withdrawn in 1996, principally due to its low efficacy. Of the newer compounds, zopolrestat (2) [19] and zenarestat (3) were withdrawn from clinical trials. At present, only epalrestat (4), which was developed by Ono and launched into the Japanese market in 1992, is still available [20].…”