Tolrestat

Summary

Tolrestat (CHEMBL436) is an approved small-molecule EC 1.1.1.21 (aldehyde reductase) inhibitor (ATC A10XA01) targeting AKR1B1; indicated across 1 condition including diabetes mellitus.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: A10XA01
• Targets: 1 (AKR1B1)
• Indications: 1 condition
• Chemistry: 357.3 Da · C16H14F3NO3S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL436
Name	Tolrestat
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	53359
ChEBI	CHEBI:48549
ATC	A10XA01
Molecular formula	C16H14F3NO3S
Molecular weight	357.3
InChIKey	LUBHDINQXIHVLS-UHFFFAOYSA-N

SMILES: CN(CC(=O)O)C(=S)C1=CC=CC2=C1C=CC(=C2C(F)(F)F)OC

IUPAC name: 2-[[6-methoxy-5-(trifluoromethyl)naphthalene-1-carbothioyl]-methylamino]acetic acid

Pharmacological roles (ChEBI): EC 1.1.1.21 (aldehyde reductase) inhibitor.

Also known as: Alredase, AY-27,773, AY-27773, Alderase, Tolrestat, tolrestat, TOLRESTAT, SID144206867

Patent coverage: 1,042 distinct patent families (3,768 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 3,714 (99%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
AKR1B1	aldo-keto reductase family 1 member B	Inhibition	7.33	1.1%	P15121

Broader ChEMBL bioactivity targets: 9 (assay-derived). Sample: Aldo-keto reductase family 1 member C21, Aldo-keto reductase family 1 member B1, Aldo-keto reductase family 1 member A1, Aldo-keto reductase family 1 member B1, Aldo-keto reductase family 1 member B1, Aldo-keto reductase family 1 member A1, Aldo-keto reductase family 1 member A1, Aldo-keto reductase family 1 member B1, Aldo-keto reductase family 1 member B10.

Bioactivity

ChEMBL activities: 40 potent at pChembl ≥ 5 of 42 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P07943	8.7	IC50	2	nM	CHEMBL_ACT_370514
P07943	8.54	IC50	2.9	nM	CHEMBL_ACT_503310
AKR1B1	8	IC50	10	nM	CHEMBL_ACT_18093249
AKR1B1	8	IC50	10	nM	CHEMBL_ACT_3357322
AKR1B10	7.94	IC50	11.6	nM	CHEMBL_ACT_2151206
AKR1B1	7.89	IC50	13	nM	CHEMBL_ACT_1505638
AKR1B1	7.85	IC50	14	nM	CHEMBL_ACT_29120149
P80276	7.82	IC50	15	nM	CHEMBL_ACT_1263515
P80276	7.8	IC50	16	nM	CHEMBL_ACT_230522
AKR1B1	7.62	IC50	23.9	nM	CHEMBL_ACT_308983
P80276	7.52	IC50	30	nM	CHEMBL_ACT_1468032
P16116	7.48	IC50	33	nM	CHEMBL_ACT_1003995
P16116	7.48	IC50	33	nM	CHEMBL_ACT_308981
P16116	7.47	IC50	34	nM	CHEMBL_ACT_1074579
AKR1B1	7.46	IC50	35	nM	CHEMBL_ACT_1060906
P16116	7.46	IC50	35	nM	CHEMBL_ACT_291520
P16116	7.46	IC50	35	nM	CHEMBL_ACT_472319
P16116	7.46	IC50	35	nM	CHEMBL_ACT_910580
AKR1B1	7.4	IC50	40	nM	CHEMBL_ACT_2139918
P07943	7.34	IC50	46	nM	CHEMBL_ACT_92689
AKR1B1	7.33	IC50	47	nM	CHEMBL_ACT_166000
AKR1B10	7.3	Ki	50	nM	CHEMBL_ACT_12095092
P07943	7.3	IC50	50	nM	CHEMBL_ACT_18152790
P07943	7.3	IC50	50	nM	CHEMBL_ACT_286384
AKR1B10	7.3	IC50	50	nM	CHEMBL_ACT_29120155
P07943	7.3	IC50	50	nM	CHEMBL_ACT_3196728
P07943	7.3	IC50	50	nM	CHEMBL_ACT_92690
AKR1B10	7.27	IC50	54	nM	CHEMBL_ACT_18093248
AKR1B10	7.27	IC50	54	nM	CHEMBL_ACT_3357313
AKR1A1	7.19	IC50	65	nM	CHEMBL_ACT_25529946

Target pathways

Aggregated over 1 target gene(s): AKR1B1.

Top Reactome pathways

9 total, by targets touching each:

Pathway	Targets	Genes
Metabolism	1	AKR1B1
Metabolism of steroid hormones	1	AKR1B1
Pregnenolone biosynthesis	1	AKR1B1
Metabolism of lipids	1	AKR1B1
Fructose metabolism	1	AKR1B1
Fructose biosynthesis	1	AKR1B1
Galactose catabolism	1	AKR1B1
Metabolism of carbohydrates and carbohydrate derivatives	1	AKR1B1
Metabolism of steroids	1	AKR1B1

Dominant GO biological processes

GO term	Targets
retinoid metabolic process	1
epithelial cell maturation	1
renal water homeostasis	1
carbohydrate metabolic process	1
C21-steroid hormone biosynthetic process	1
regulation of urine volume	1
negative regulation of apoptotic process	1
daunorubicin metabolic process	1
doxorubicin metabolic process	1
fructose biosynthetic process	1
cellular hyperosmotic salinity response	1
metanephric collecting duct development	1
lipid metabolic process	1
prostaglandin metabolic process	1
retinol metabolic process	1

Indications & clinical

Indications

1 indication (1 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
diabetes mellitus	4	MONDO:0005015	EFO:0000400

Clinical trials

Total trials: 0.

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

36 molecules share ≥1 primary target. Top 36 by shared-target count:

Molecule	Source	Status	Shared targets
FOLIC ACID	ChEMBL + PubChem	Phase 4 (approved)	AKR1B1
EPALRESTAT	ChEMBL	Phase 4 (approved)	AKR1B1
ESTRADIOL	ChEMBL	Phase 4 (approved)	AKR1B1
ESTRONE	ChEMBL	Phase 4 (approved)	AKR1B1
INDOMETHACIN	ChEMBL	Phase 4 (approved)	AKR1B1
MEFENAMIC ACID	ChEMBL	Phase 4 (approved)	AKR1B1
NITAZOXANIDE	ChEMBL	Phase 4 (approved)	AKR1B1
SULINDAC	ChEMBL	Phase 4 (approved)	AKR1B1
TOLMETIN	ChEMBL	Phase 4 (approved)	AKR1B1
CAFFEIC ACID	ChEMBL	Phase 3	AKR1B1
CURCUMIN	ChEMBL	Phase 3	AKR1B1
GOSSYPOL	ChEMBL	Phase 3	AKR1B1
QUERCETIN	ChEMBL	Phase 3	AKR1B1
RANIRESTAT	ChEMBL	Phase 3	AKR1B1
RESVERATROL	ChEMBL	Phase 3	AKR1B1
SORBINIL	ChEMBL	Phase 3	AKR1B1
ALRESTATIN	ChEMBL	Phase 2	AKR1B1
AZD1981	ChEMBL	Phase 2	AKR1B1
CHLOROGENIC ACID	ChEMBL	Phase 2	AKR1B1
ELLAGIC ACID	ChEMBL	Phase 2	AKR1B1
FIDARESTAT	ChEMBL	Phase 2	AKR1B1
FLUFENAMIC ACID	ChEMBL	Phase 2	AKR1B1
GENISTEIN	ChEMBL	Phase 2	AKR1B1
HYMECROMONE	ChEMBL	Phase 2	AKR1B1
IMIRESTAT	ChEMBL	Phase 2	AKR1B1
ISOQUERCETIN	ChEMBL	Phase 2	AKR1B1
LIDORESTAT	ChEMBL	Phase 2	AKR1B1
LUTEOLIN	ChEMBL	Phase 2	AKR1B1
MINALRESTAT	ChEMBL	Phase 2	AKR1B1
OXEPINAC	ChEMBL	Phase 2	AKR1B1
PONALRESTAT	ChEMBL	Phase 2	AKR1B1
SEPRANOLONE	ChEMBL	Phase 2	AKR1B1
TIOPINAC	ChEMBL	Phase 2	AKR1B1
URSOLIC ACID	ChEMBL	Phase 2	AKR1B1
ZENARESTAT	ChEMBL	Phase 2	AKR1B1
ZOPOLRESTAT	ChEMBL	Phase 2	AKR1B1