Epalrestat

Summary

Epalrestat (CHEMBL56337) is an approved small-molecule EC 1.1.1.21 (aldehyde reductase) inhibitor targeting CYP4A11; indicated across 2 conditions including breast neoplasm and charcot-marie-tooth disease.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• Targets: 1 (CYP4A11)
• Indications: 2 conditions
• Clinical trials: 6
• Chemistry: 319.4 Da · C15H13NO3S2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL56337
Name	Epalrestat
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	1549120
ChEBI	CHEBI:31539
Molecular formula	C15H13NO3S2
Molecular weight	319.4
InChIKey	CHNUOJQWGUIOLD-NFZZJPOKSA-N

SMILES: C/C(=C\C1=CC=CC=C1)/C=C\2/C(=O)N(C(=S)S2)CC(=O)O

IUPAC name: 2-[(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid

ChEBI definition: A monocarboxylic acid that is 1,3-thiazolidine which is substituted on the nitrogen by a carboxymethyl group, at positions 2 and 4 by thioxo and oxo groups, respectively, and at position 5 by a 2-methyl-3-phenylprop-2-en-1-ylidene group. It is an inhibitor of aldose reductase (which catalyses the conversion of glucose to sorbitol) and is used for the treatment of some diabetic complications, including neuropathy.

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

Also known as: Aldonil, Aldorin, Epalrestat, Kinedak, Tanglin, Epalrestate, SID26664249, SID26758035, Eparlestat, EPALRESTAT, epalrestat, EpalrestatÊ

Parent form; salt/anhydrous children: CHEMBL4297277

Patent coverage: 61 distinct patent families (110 SureChEMBL compound mentions), from 1 matched compound structure(s). 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
CYP4A11	CYP4A11	Inhibition	5.74	0.2%	Q02928

Broader ChEMBL bioactivity targets: 47 (assay-derived). Sample: Microtubule-associated protein tau, Fructose-bisphosphate aldolase, Prelamin-A/C, NPC intracellular cholesterol transporter 1, ATP-binding cassette sub-family C member 4, Neuronal acetylcholine receptor subunit alpha-4, Vasopressin V1a receptor, 5-hydroxytryptamine receptor 3A, Aldo-keto reductase family 1 member B1, Alpha-2C adrenergic receptor, Alpha-2B adrenergic receptor, Equilibrative nucleoside transporter 1, Bile acid receptor, Thromboxane A2 receptor, Beta-1 adrenergic receptor, 5-hydroxytryptamine receptor 1A, Muscarinic acetylcholine receptor M1, D(2) dopamine receptor, Sodium-dependent noradrenaline transporter, Aldo-keto reductase family 1 member A1.

Bioactivity

ChEMBL activities: 76 potent at pChembl ≥ 5 of 104 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
AKR1B1	8	IC50	10	nM	CHEMBL_ACT_1035306
P07943	8	IC50	10	nM	CHEMBL_ACT_1119894
P07943	7.89	IC50	13	nM	CHEMBL_ACT_491437
AKR1B1	7.7	IC50	20	nM	CHEMBL_ACT_29120151
P07943	7.68	IC50	21	nM	CHEMBL_ACT_1114338
GSK3B	7.68	IC50	21	nM	CHEMBL_ACT_25486114
AKR1B1	7.68	IC50	21	nM	CHEMBL_ACT_3357323
P07943	7.68	IC50	21	nM	CHEMBL_ACT_865089
P07943	7.64	IC50	23	nM	CHEMBL_ACT_84419
P07943	7.51	IC50	31	nM	CHEMBL_ACT_19254015
P07943	7.5	IC50	32	nM	CHEMBL_ACT_7675544
AKR1B10	7.45	IC50	35.2	nM	CHEMBL_ACT_20599906
AKR1B10	7.41	IC50	39.3	nM	CHEMBL_ACT_20599907
P07943	7.35	IC50	45	nM	CHEMBL_ACT_22416903
AKR1B1	7.18	IC50	66.5	nM	CHEMBL_ACT_22836866
P07943	7.17	IC50	67	nM	CHEMBL_ACT_10846607
P07943	7.16	IC50	70	nM	CHEMBL_ACT_2213744
P07943	7.14	IC50	72	nM	CHEMBL_ACT_2534012
P07943	7.14	IC50	72	nM	CHEMBL_ACT_8009311
P07943	7.09	IC50	81	nM	CHEMBL_ACT_20668411
P07943	7.08	IC50	84	nM	CHEMBL_ACT_15201319
P07943	7.07	IC50	85.68	nM	CHEMBL_ACT_15697789
AKR1B1	7.07	IC50	85	nM	CHEMBL_ACT_16851280
P07943	7.07	IC50	86	nM	CHEMBL_ACT_18012297
AKR1B1	7.03	IC50	93.9	nM	CHEMBL_ACT_18212152
P07943	7	IC50	100	nM	CHEMBL_ACT_13870576
AKR1B1	7	IC50	100	nM	CHEMBL_ACT_25614865
AKR1B1	7	IC50	100	nM	CHEMBL_ACT_8023957
AKR1B1	6.99	IC50	102	nM	CHEMBL_ACT_18934373
P07943	6.97	IC50	108.1	nM	CHEMBL_ACT_22928558
AKR1B1	6.96	IC50	110	nM	CHEMBL_ACT_20599888
AKR1B1	6.96	IC50	110	nM	CHEMBL_ACT_20599898
P07943	6.92	IC50	120	nM	CHEMBL_ACT_14664403
P07943	6.92	IC50	120	nM	CHEMBL_ACT_7967426
P07943	6.89	IC50	130	nM	CHEMBL_ACT_16583194
AKR1B1	6.82	IC50	150	nM	CHEMBL_ACT_20599903
P07943	6.77	IC50	170	nM	CHEMBL_ACT_10846478
P07943	6.77	IC50	170	nM	CHEMBL_ACT_12165118
P16116	6.77	IC50	170	nM	CHEMBL_ACT_14671221
P16116	6.77	IC50	170	nM	CHEMBL_ACT_5128034
P16116	6.77	IC50	170	nM	CHEMBL_ACT_6255407
P07943	6.64	IC50	227	nM	CHEMBL_ACT_18461229
P07943	6.62	IC50	240	nM	CHEMBL_ACT_29138654
P07943	6.6	IC50	250	nM	CHEMBL_ACT_15232010
P07943	6.6	IC50	250	nM	CHEMBL_ACT_29138659
AKR1A1	6.49	IC50	325	nM	CHEMBL_ACT_25529945
AKR1B10	6.48	IC50	330	nM	CHEMBL_ACT_29120157
AKR1B10	6.48	IC50	330	nM	CHEMBL_ACT_3357314
AKR1B10	6.48	IC50	330	nM	CHEMBL_ACT_8023978
P07943	6.29	IC50	510	nM	CHEMBL_ACT_19184658
P07943	6.28	IC50	530	nM	CHEMBL_ACT_19184852
AKR1B1	6.21	IC50	620	nM	CHEMBL_ACT_19184532
P07943	6.07	IC50	860	nM	CHEMBL_ACT_19184755
Q5RJP0	5.92	IC50	1198	nM	CHEMBL_ACT_22416888
P07943	5.82	IC50	1500	nM	CHEMBL_ACT_1114339
AGTR1	5.82	AC50	1500	nM	CHEMBL_ACT_25176616
P50578	5.82	IC50	1500	nM	CHEMBL_ACT_491438
P51635	5.82	IC50	1500	nM	CHEMBL_ACT_865090
ABCB11	5.8	AC50	1600	nM	CHEMBL_ACT_25126839
P51635	5.67	IC50	2140	nM	CHEMBL_ACT_29138653
P07943	5.65	IC50	2257	nM	CHEMBL_ACT_19254006
P51635	5.62	IC50	2370	nM	CHEMBL_ACT_29138665
AKR1A1	5.58	IC50	2600	nM	CHEMBL_ACT_3357332
AKR1A1	5.58	IC50	2600	nM	CHEMBL_ACT_8023929
P07943	5.49	IC50	3210	nM	CHEMBL_ACT_19184568
NPC1	5.45	Potency	3548	nM	CHEMBL_ACT_4752501
NR1I3	5.44	AC50	3600	nM	CHEMBL_ACT_25164306
NR1H4	5.4	AC50	4000	nM	CHEMBL_ACT_25202130
P07943	5.3	IC50	5000	nM	CHEMBL_ACT_22928583
ABCC4	5.19	IC50	6500	nM	CHEMBL_ACT_18130799
HTR2C	5.19	AC50	6400	nM	CHEMBL_ACT_25131429
ADRA2B	5.12	AC50	7500	nM	CHEMBL_ACT_25143321
MAPT	5.1	Potency	7943	nM	CHEMBL_ACT_4023149
ADRA2C	5.09	AC50	8200	nM	CHEMBL_ACT_25147484
OPRD1	5.05	AC50	9000	nM	CHEMBL_ACT_25153687
DRD2	5.04	AC50	9100	nM	CHEMBL_ACT_25139942

Target pathways

Aggregated over 1 target gene(s): CYP4A11.

Top Reactome pathways

6 total, by targets touching each:

Pathway	Targets	Genes
PPARA activates gene expression	1	CYP4A11
Fatty acids	1	CYP4A11
Miscellaneous substrates	1	CYP4A11
Eicosanoids	1	CYP4A11
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	CYP4A11
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	CYP4A11

Dominant GO biological processes

GO term	Targets
long-chain fatty acid metabolic process	1
kidney development	1
renal water homeostasis	1
pressure natriuresis	1
fatty acid metabolic process	1
leukotriene metabolic process	1
arachidonate metabolic process	1
epoxygenase P450 pathway	1
oxylipin biosynthetic process	1
positive regulation of icosanoid secretion	1
linoleic acid metabolic process	1
icosanoid biosynthetic process	1
lauric acid metabolic process	1
sodium ion homeostasis	1
omega-hydroxylase P450 pathway	1

Indications & clinical

Indications

2 diseases in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
breast neoplasm	2	MONDO:0021100	MONDO:0007254
Charcot-Marie-Tooth disease	2	MONDO:0015626	MONDO:0015626

Clinical trials

Total trials: 6.

Phase distribution

Phase	Trials
PHASE2	3
PHASE4	1
PHASE3	1
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05184049	PHASE4	UNKNOWN	Effects of Epalrestat on Peripheral Neuropathy and Central Nervous System in Diabetic Patients
NCT06201611	PHASE2/PHASE3	RECRUITING	Evaluating a Nitric Oxide Generator, Nebivolol as a Disease Modifier in Patients With Diabetic Neuropathy.
NCT04925960	PHASE3	TERMINATED	Oral Epalrestat Therapy in Pediatric Subjects With PMM2-CDG
NCT07557914	PHASE2	NOT_YET_RECRUITING	Epalrestat Combined With HAIC, Donafenib and Tislelizumab as First-line Treatment for Patients With Unresectable HCC and Diabetes - A Multicenter, Prospective, Single-arm Clinical Study
NCT03244358	PHASE2	TERMINATED	Evaluation of Epalrestat in Metastatic Triple-negative Breast Cancer
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment

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.

20 molecules share ≥1 primary target. Top 20 by shared-target count:

Molecule	Source	Status	Shared targets
PAZOPANIB	ChEMBL	Phase 4 (approved)	CYP4A11
Aprepitant	PubChem	Approved	CYP4A11
Cenobamate	PubChem	Approved	CYP4A11
Dabrafenib	PubChem	Approved	CYP4A11
Diclofenac	PubChem	Approved	CYP4A11
Fluconazole	PubChem	Approved	CYP4A11
Genistein	PubChem	Approved	CYP4A11
Nevirapine	PubChem	Approved	CYP4A11
Oritavancin	PubChem	Approved	CYP4A11
Panobinostat	PubChem	Approved	CYP4A11
Phenobarbital	PubChem	Approved	CYP4A11
Pioglitazone	PubChem	Approved	CYP4A11
Pitolisant	PubChem	Approved	CYP4A11
Prednisone	PubChem	Approved	CYP4A11
rifampin	PubChem	Approved	CYP4A11
Safinamide	PubChem	Approved	CYP4A11
Tazemetostat	PubChem	Approved	CYP4A11
Tecovirimat	PubChem	Approved	CYP4A11
Telotristat Ethyl	PubChem	Approved	CYP4A11
Vemurafenib	PubChem	Approved	CYP4A11