Tolbutamide

Summary

Tolbutamide (CHEMBL782) is an approved small-molecule hypoglycemic agent (ATC V04CA01) targeting KCNJ8 and KCNJ11; indicated across 8 conditions including diabetes mellitus and type 2 diabetes mellitus.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: V04CA01 (+1 more)
• Targets: 2 (KCNJ8, KCNJ11)
• Indications: 8 conditions
• Clinical trials: 16
• Chemistry: 270.35 Da · C12H18N2O3S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL782
Name	Tolbutamide
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	5505
ChEBI	CHEBI:27999
ATC	V04CA01, A10BB03
Molecular formula	C12H18N2O3S
Molecular weight	270.35
InChIKey	JLRGJRBPOGGCBT-UHFFFAOYSA-N

SMILES: CCCCNC(=O)NS(=O)(=O)C1=CC=C(C=C1)C

IUPAC name: 1-butyl-3-(4-methylphenyl)sulfonylurea

ChEBI definition: An N-sulfonylurea that consists of 1-butylurea having a tosyl group attached at the 3-position.

Pharmacological roles (ChEBI): hypoglycemic agent, potassium channel blocker, insulin secretagogue.

Other ChEBI roles (chemical / environmental): human metabolite.

Also known as: Arkozal, Butamide, Diabetamid, Glyconon, Ipoglicone, NSC-23813, NSC-87833, Orinase, Pramidex, Rastinon, Tolbutamida, Tolbutamide

Parent form; salt/anhydrous children: CHEMBL1200874

Patent coverage: 11,409 distinct patent families (43,220 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
KCNJ8	Kir6.1			0%	Q15842
KCNJ11	Kir6.2			0.1%	Q14654

Broader ChEMBL bioactivity targets: 10 (assay-derived). Sample: Tyrosyl-DNA phosphodiesterase 1, Prelamin-A/C, Solute carrier family 22 member 6, Thyrotropin receptor, Muscarinic acetylcholine receptor M1, Albumin, Cytochrome P450 2C9, Aldehyde dehydrogenase 1A1, Lethal factor, Albumin.

Bioactivity

ChEMBL activities: 10 potent at pChembl ≥ 5 of 17 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P08482	7.55	Potency	28.2	nM	CHEMBL_ACT_4803359
LMNA	6.65	Potency	223.9	nM	CHEMBL_ACT_3624431
CYP2C9	6.42	IC50	380	nM	CHEMBL_ACT_24822372
CYP2C9	6.42	IC50	380	nM	CHEMBL_ACT_25593405
CYP2C9	6.39	IC50	404	nM	CHEMBL_ACT_24740404
CYP2C9	6.38	IC50	421	nM	CHEMBL_ACT_25502128
P15917	5.4	Potency	3981	nM	CHEMBL_ACT_4651666
ALB	5.22	Kd	6026	nM	CHEMBL_ACT_2158020
CYP2C9	5.11	IC50	7690	nM	CHEMBL_ACT_26109720
P02770	5.1	Kd	7970	nM	CHEMBL_ACT_15448293

Target pathways

Aggregated over 2 target gene(s): KCNJ8, KCNJ11.

Top Reactome pathways

17 total, by targets touching each:

Pathway	Targets	Genes
Neuronal System	2	KCNJ11, KCNJ8
ATP sensitive Potassium channels	2	KCNJ11, KCNJ8
Inwardly rectifying K+ channels	2	KCNJ11, KCNJ8
Potassium Channels	2	KCNJ11, KCNJ8
Metabolism	1	KCNJ11
Integration of energy metabolism	1	KCNJ11
Disease	1	KCNJ11
Transport of small molecules	1	KCNJ11
ABC-family protein mediated transport	1	KCNJ11
Muscle contraction	1	KCNJ11
Regulation of insulin secretion	1	KCNJ11
Cardiac conduction	1	KCNJ11
Ion homeostasis	1	KCNJ11
ABC transporter disorders	1	KCNJ11
Disorders of transmembrane transporters	1	KCNJ11
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	KCNJ11
Defective ABCC8 can cause hypo- and hyper-glycemias	1	KCNJ11

Dominant GO biological processes

GO term	Targets
response to hypoxia	2
response to ischemia	2
ventricular cardiac muscle tissue development	2
potassium ion transport	2
apoptotic process	2
determination of adult lifespan	2
response to xenobiotic stimulus	2
response to ATP	2
regulation of monoatomic ion transmembrane transport	2
CAMKK-AMPK signaling cascade	2
potassium ion transmembrane transport	2
obsolete inorganic cation transmembrane transport	2
response to resveratrol	2
potassium ion import across plasma membrane	2
action potential	2

Indications & clinical

Indications

8 indications (2 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
type 2 diabetes mellitus	4	MONDO:0005148	MONDO:0005148
lymphoma	1	MONDO:0005062	EFO:0000574
neoplasm	1	MONDO:0005070	EFO:0000616
chronic hepatitis C virus infection	1	MONDO:0005354	EFO:0004220

3 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 16.

Phase distribution

Phase	Trials
PHASE1	15
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00185003	PHASE1	COMPLETED	Blockade of Vascular Potassium Channels During Human Endotoxemia
NCT00930306	PHASE1	COMPLETED	AZD2066 Cocktail Study
NCT01185548	PHASE1	TERMINATED	A Drug Interaction Study of Tasisulam in Patients With Advanced Cancer or Lymphoma
NCT01218620	PHASE1	COMPLETED	Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced Solid Tumors
NCT01525628	PHASE1	COMPLETED	Drug Drug Interaction Study Between BI 201335 and BI 207127 in Chronic Hepatitis C Infected Patients
NCT02182401	PHASE1	TERMINATED	Multiple Doses of BI 207127 NA, BI 201335 NA Followed by the Combination of BI 207127 NA and BI 201335 NA in Healthy Male Volunteers
NCT02211079	PHASE1	COMPLETED	A Study to Assess Effect of JNJ-54861911 on Pharmacokinetics of Cocktail Representatives for Cytochrome P450 (CYP) 3A4, CYP2B6, CYP2C9, and CYP1A2 Substrates
NCT02473627	PHASE1	COMPLETED	A PHASE 1, OPEN-LABEL, CROSS-OVER, FIXED SEQUENCE STUDY TO EVALUATE THE EFFECT OF MULTIPLE DOSES OF DS-1971A ON THE SINGLE DOSE PHARMACOKINETICS OF PROBE SUBSTRATES FOR CYP2B6, CYP2C8, CYP2C9, CYP2C19 AND CYP3A4 ENZYMES IN HEALTHY MALE AND FEMALE SUBJECTS
NCT03103568	PHASE1	COMPLETED	A Study to Investigate the Potential Influence of Nitisinone on the Metabolism and the Transport of Other Drugs in Healthy Volunteers
NCT03291288	PHASE1	COMPLETED	Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)
NCT03457597	PHASE1	COMPLETED	Study in Healthy Subjects to Determine the Effect of Relacorilant on Exposure to Probe Substrates for Cytochrome P450s
NCT03716427	PHASE1	COMPLETED	Drug Interaction Study of CT1812 in Healthy Volunteers
NCT03723395	PHASE1	COMPLETED	A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib
NCT03948243	PHASE1	COMPLETED	Licorice Botanical Dietary Supplements - Metabolism and Safety in Women
NCT05097716	PHASE1	COMPLETED	Study to Evaluate the Effect of Multiple-Dose Ritlecitinib on the Pharmacokinetics (PK) of Tolbutamide
NCT02515526	Not specified	COMPLETED	Effect of Acute Ethanol Consumption on The Activity of Major Cytochrome P450 Enzymes, NAT2 and P-glycoprotein

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

PharmGKB dosing guidelines (2) — CPIC / DPWG genotype-guided dosing for this drug (drug × pharmacogene):

Guideline	Source	Gene(s)	Dosing	Recommendation
Annotation of DPWG Guideline for tolbutamide and CYP2C9	DPWG	CYP2C9
Annotation of CPIC Guideline for aminosalicylic acid, chloramphenicol,	CPIC	G6PD

PharmGKB also curates 5 clinical and 28 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

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.

8 molecules share ≥1 primary target. Top 8 by shared-target count:

Molecule	Source	Status	Shared targets
glyburide	ChEMBL + PubChem	Phase 4 (approved)	KCNJ11, KCNJ8
CROMAKALIM	ChEMBL	Phase 2	KCNJ11, KCNJ8
DIAZOXIDE	ChEMBL + PubChem	Phase 4 (approved)	KCNJ11
PROPAFENONE	ChEMBL + PubChem	Phase 4 (approved)	KCNJ11
PINACIDIL	ChEMBL	Phase 4 (approved)	KCNJ11
CLAMIKALANT	ChEMBL	Phase 2	KCNJ11
TIFENAZOXIDE	ChEMBL	Phase 2	KCNJ11
Berberine Chloride	PubChem	Approved	KCNJ11