Orally active aldose reductase inhibitors: indazoleacetic, oxopyridazineacetic, and oxopyridopyridazineacetic acid derivatives

Abstract

Benzothiazole side chains featured in zopolrestat (1a) and its congeners were incorporated into oxophthalazineacetic acid replacements, including indazole, pyridazinone, and pyridopyridazinone with a pendant acetic acid moiety. Potent aldose reductase inhibition activity among resulting compounds is as widespread as it is in the earlier zopolrestat series, thus lending further support to our hypothesis that there is a binding site on the aldose reductase enzyme with strong affinity for benzothiazoles. Representative new compounds 1-[(5,7-difluoro-2-benzothiazolyl)-methyl]-1H-indazoleacetic acid (62), [6-[[5-(trifluoromethyl)benzothiazol-2-yl]methyl]-8-oxo- 6H-pyrido[2,3-d]-pyridazin-5-yl]acetic acid (70), 3,4-dihydro-4-oxo-5,6-dimethyl-3-[(5,7-difluorobenzothiazol-2-yl) methyl]-1-pyridazineacetic acid (79), and 3,4-dihydro-4-oxo-5,6-cyclohexano-3-[[5-(trifluoromethyl) benzothiazol-2-yl]-methyl]-1-pyridazineacetic acid (82) are potent aldose reductase inhibitors with IC50s of 30, 2.1, 5, and 52.2 nM, respectively. The best of these compounds, 79 and 82, also inhibit accumulation of sorbitol in rat sciatic nerve in a model of diabetic complications, when administered orally at 10 mg/kg. The inhibition values are 76 and 61%, respectively. In addition to benzothiazole, we have examined its surrogates effective in potentiating aldose reductase inhibition activity, including benzoxazole and aryl[1,2,4]oxadiazole. Structure-activity relationships emerging from this program are also discussed.

Highly Potent and Specific GSK‐3β Inhibitors That Block Tau Phosphorylation and Decrease α‐Synuclein Protein Expression in a Cellular Model of Parkinson's Disease

“…The indazolyl-3-acetamides 4 were prepared from 2-nitrobenzaldehyde and 5-chloro-2-nitrobenzaldehyde according to published procedures. [13,14] A solution of tBuOK in THF (1.0 m, 1.0 mL) was added dropwise to a suspension of indazolyl-3-acetamide (4: Y= H, R 2 = H; 42 mg, 0.24 mmol) and indolyl-3-glyoxylate (3: X= 5-Cl, R 1 = 3-methoxyethyl; 92 mg, 0.31 mmol) in dry THF (2.5 mL) at 0 8C, and the reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched with HCl (12 n) and diluted with EtOAc.…”

“…The required reaction partners, the indazolyl-3-acetamides 4, were prepared from the appropriate ortho-nitrobenzaldehyde according to a previously published procedure. [13,14] The appendage of an alkyl side chain onto the indazole ring (as in compound 11) was carried out by treatment of the acetamides 4 with 2-bromoethyl methyl ether in the presence of sodium hydroxide followed by column chromatography.…”

Diabetes complications and their potential prevention: Aldose reductase inhibition and other approaches

“…Aldose Reductase Inhibitors: Carboxylic Acid dose reductase with strong affinity for the benzothiazole moiety. 30 This hypothesis was later confirmed by the resolution of the crystal structure of Zopolrestat complexed with ALR2. 31 Starting from this evidence, several articles appeared reporting new compounds having, besides a carboxylic acid moiety, a benzothiazole ring.…”

Biological Potential and Chemical Properties of Pyridine and Piperidine Fused Pyridazine Compounds: Pyridopyridazine a Versatile Nucleus

“…Pyridopyridazines and pyridopyridazinones showed wide spectrum of biological activities. Recently the pyridazinone ring has been extensively studied in the search for new and selective drug molecules [27][28][29][30][31][32] . In contrast to the phthalazinones, their aza derivatives, pyridopyridazinones are relatively little studied.…”

“…Some pyridopyridazine derivatives were exhibited antitumor activities 30 . Pyridopyridazine nucleus showed antiasthmatic 31 , antidiabetic 32 , antituberculosis 33 and antimicrobial activities 34 .…”