Discovery of 3-[(4,5,7-Trifluorobenzothiazol-2-yl)methyl]indole-N-acetic Acid (Lidorestat) and Congeners as Highly Potent and Selective Inhibitors of Aldose Reductase for Treatment of Chronic Diabetic Complications

Abstract

Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC(50) of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED(50)'s of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t(1/2), 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (C(max) in sciatic nerve and eye are 2.36 and 1.45 mug equiv/g, respectively, when dosed with [(14)C]lidorestat at 10 mg/kg po).

Aldose Reductase Inhibitors as Potential Therapeutic Drugs of Diabetic Complications

“…These ligand-dependent conformations indicate a remarkable induced fit or flexibility of the active site. Nevertheless, at least three distinct binding pockets in the active site can be proposed as shown in Figure 2 according to a number of studies on crystal structures of AR by X-ray crystallography and mutagenesis [30,[33][34][35][36][37][38]. The first is usually occupied by the anion head of ligand and thus named "anion binding pocket".…”

“…Ponalrestat was withdrawn from clinical trials due to lack of efficacy. Besides, a number of potent ARIs were recently designed and synthesized based on various chemical core structures including (benzothiazol-2-yl)methylindole (lidorestat) [36], naphtho [1,2-d]isothiazole [55], oxadiazole [56], aromatic thiadiazine-1,1-dioxide [57,58], and quinoxalinone [59]. All of them bear a chemical group of acetic acid on the core.…”

Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship

“…Lidorestat ( Figure 2) and its substitution congeners, derivatives of 1-indole acetic acid (Van Zandt et al 2005, 2006, belong among the most efficient inhibitors of ALR2 with IC 50 values in the nmol/l region and with very good ALR2/ALR1 selectivity values. We used the available structure of lidorestat-ALR2 complex (pdb structure 1z3n) for comparative molecular modeling studies of 1-vs. 3-indole acetic acids.…”

Convenient Approach for the One-Pot, Three-Component Synthesis of 1-(Benzothiazolylamino)Methyl-2- Naphthol Using Citric Acid as a Green Catalyst

“…10,11 2-AminoBenzothiazoles as inimitable frames are presented a broad spectrum of pharmacological and biological properties. 12 Simplicity in electron transfer in the firefly luciferine cycle is reason of their different acts, 13 through antitumor, 14 and antidiabetic activity 15 to Alzheimer disease tracer, 16 and anticancer agent in pharmaceutical chemistry. 17 Also, benzothiazoles are commercially momentous as reactive dyes, 18 hair dyes, 19 agrochemical fungicides, acaricides, herbicides, insecticides, plant desiccants, and defolicants.…”