N -(Aroyl)- N -(arylmethyloxy)-α-alanines: Selective inhibitors of aldose reductase

Abstract

Aldose reductase (ALR2), a NADPH-dependent reductase, is the first and rate-limiting enzyme of the polyol pathway of glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications. In the last decades, this enzyme has been targeted for inhibition but despite the numerous efforts made to identify potent and safe ALR2 inhibitors, many clinical candidates have been a failure. For this reason the research of new ALR2 inhibitors highly effective, selective and with suitable pharmacokinetic properties is still of great interest. In this paper some new N-(aroyl)-N-(arylmethyloxy)alanines have been synthesized and tested for their ability to inhibit ALR2. Some of the synthesized compounds exhibit IC in the low micromolar range and all have proved to be highly selective towards ALR2. The N-(aroyl)-N-(arylmethyloxy)-α-alanines are a promising starting point for the development of new ALR2 selective drugs with the aim of delaying the onset of diabetic complications.

Comparative transcriptome analysis reveals significant metabolic alterations in eri-silkworm (Samia cynthia ricini) haemolymph in response to 1-deoxynojirimycin

“…Diacylglycerol kinase isoforms regulate signal transduction and lipid metabolism and have divergent functional roles in distinct tissues [ 43 ]. AR is an NADPH-dependent reductase that is the first rate-limiting enzyme of the polyol pathway in glucose metabolism and is implicated in the pathogenesis of secondary diabetic complications [ 44 ]. In the last few decades, this enzyme has been used as a target to prevent cellular inflammatory events [ 45 ].…”

Oxy-imino saccharidic derivatives as a new structural class of aldose reductase inhibitors endowed with anti-oxidant activity

“…Methyl 3,4-O-isopropylidene-6-O-tosyl-b-D-galactopyranoside was prepared according to the reported procedure 16 . O-(4-methoxybenzyl)hydroxylamine hydrochloride (7a) 17 and O-(4-trifluoromethylbenzyl)hydroxylamine hydrochloride (7 b) 18 were prepared according to literature by alkylation of N-hydroxyphtalimide with substituted benzyl bromide but the corresponding imides obtained were treated with NH 3 /MeOH 7 N instead of hydrazine hydrate and then with hydrochloride in ethyl ether to obtain the hydrochlorides 7a and 7b.…”

“…6a can be stored at -20 C, under argon atmosphere for several months.The reaction of derivative 6a (Scheme 2) with the O-(4-methoxybenzyl)hydroxylamine hydrochloride 7a17 in a 3:1 CHCl 3 -H 2 O mixture at 60 C (4 h) afforded, after purification by flash chromatography the corresponding arylmethyloxyimino derivatives 8 in low yield as mixture of E/Z isomers [38% (E)-8:(Z)-8 ¼ 63:37]. To reduce reaction times and increase yields, the reactions of 6a (Scheme 2) with 7a 17 or 7b 18 was performed in a 3:1 CHCl 3 -H 2 O mixture under MW irradiation at 40 C (20 min).…”

Aldose reductase inhibitors: 2013-present

“…From the medicinal chemist's point of view, the marked induced-fit adaptability of ALR2 is attracting and fascinating. Actually, as it is hard to predict the binding mode of the ligands even through docking and virtual screening, the development of novel, effective inhibitors represents an intriguing and stimulating challenge [56,57], which inevitably results in a plethora of chemically different compounds [58][59][60][61][62][63][64][65][66][67][68][69]. Those developed over the last five years, which became the main core of patents filed, have been analyzed and reviewed hereafter grouped on the basis of their origin: natural derivatives, semi-synthetic compounds obtained through suitable modifications of naturally 9 occurring scaffolds, and synthetic inhibitors.…”