act-132577 profile

aprocitentan: a macitentan metabolite [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

ACT-132577 : A member of the class of sulfamides in which one of the amino groups of sulfonamide is substituted by a 5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl group. An active metabolite of macitentan (obtained by oxidative depropylation), an orphan drug used for the treatment of pulmonary arterial hypertension. [Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

ID Source	ID
PubMed CID	25099191
CHEMBL ID	2165326
CHEBI ID	76609
SCHEMBL ID	3646065
MeSH ID	M0574406

Synonym
n-(5-(4-bromophenyl)-6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-4-pyrimidinyl)sulfuric diamide
mzi81hv01p ,
aprocitentan [usan]
aprocitentan
sulfamide, n-(5-(4-bromophenyl)-6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-4-pyrimidinyl)-
who 10552
act 132577
unii-mzi81hv01p
1103522-45-7
act-132577
SCHEMBL3646065
CHEMBL2165326 ,
chebi:76609 ,
bdbm50395672
macitentan metabolite m6
n-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}pyrimidin-4-yl]sulfuric diamide
HY-15895
aprocitentan [inn]
n-(5-(4-bromophenyl)-6-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)pyrimidin-4-yl)sulfamide
aprocitentan [who-dd]
n-(5-(4-bromophenyl)-6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-4-pyrimidinyl)-sulfamide
AKOS028114466
despropyl macitentan
NCGC00378592-01
gtpl10070
Q27146161
5-(4-bromophenyl)-4-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-6-(sulfamoylamino)pyrimidine
DB15059
n-(5-(4-bromophenyl)-6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-4-pyrimidinyl)sulfamide
act-132577; act 132577; act132577
BCP28125
aprocitentan (usan/inn)
D11441
n-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]sulfamide
AMY39078
D87138
aprocitentan (act-132577)
EX-A4419
AC-36529
A922313
[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]-ethoxy]-4-pyrimidinyl]sulfamide
SY310435
mfcd28155267
AS-82256

Excerpt	Reference	Relevance
" Aprocitentan was safe and well tolerated in both groups."	( Multiple-Dose Pharmacokinetics, Safety, and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Healthy Japanese and Caucasian Subjects. Dingemanse, J; Fontes, MSC; Sidharta, PN, 2021)	0.62

Excerpt	Reference	Relevance
"For both macitentan and its metabolite, values for Cmax were similar but a shorter half-life was determined in Japanese subjects resulting in an exposure to both compounds being approximately 15% lower in Japanese when compared to Caucasian subjects."	( Pharmacokinetics of macitentan in caucasian and Japanese subjects: the influence of ethnicity and sex. Bruderer, S; Dingemanse, J; Marjason, J; Sidharta, PN, 2013)	0.39
"A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro."	( Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions. Buchmann, S; de Kanter, R; Delahaye, S; Gnerre, C; Kohl, C; Segrestaa, J; Sidharta, PN; Treiber, A, 2016)	0.43
" Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours."	( Effects of Multiple-Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin. Dingemanse, J; Sidharta, PN, 2020)	0.56
" At steady state, maximum plasma concentration was reached at 4 and 3 hours, and elimination half-life was 49."	( Multiple-Dose Pharmacokinetics, Safety, and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Healthy Japanese and Caucasian Subjects. Dingemanse, J; Fontes, MSC; Sidharta, PN, 2021)	0.62
", body weight, age, sex, race, renal and hepatic impairment, health status (healthy volunteers vs patients with pulmonary arterial hypertension), and formulation (capsules vs tablets) on pharmacokinetic parameters."	( A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension. Bartolucci, R; Csonka, D; Dosne, AG; Magni, P; Pérez-Ruixo, JJ; Poggesi, I, 2021)	0.62
" Body weight, sex, race, renal impairment, health status, and formulation were statistically significant covariates on pharmacokinetic parameters."	( A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension. Bartolucci, R; Csonka, D; Dosne, AG; Magni, P; Pérez-Ruixo, JJ; Poggesi, I, 2021)	0.62
"The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations."	( A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension. Bartolucci, R; Csonka, D; Dosne, AG; Magni, P; Pérez-Ruixo, JJ; Poggesi, I, 2021)	0.62

Excerpt	Reference	Relevance
"This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit)."	( Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions. Buchmann, S; de Kanter, R; Delahaye, S; Gnerre, C; Kohl, C; Segrestaa, J; Sidharta, PN; Treiber, A, 2016)	0.43

Excerpt	Reference	Relevance
"The ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit both brain penetration and oral bioavailability of many chemotherapy drugs."	( A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. Ambudkar, SV; Brimacombe, KR; Chen, L; Gottesman, MM; Guha, R; Hall, MD; Klumpp-Thomas, C; Lee, OW; Lee, TD; Lusvarghi, S; Robey, RW; Shen, M; Tebase, BG, 2019)	0.51

Excerpt	Relevance	Reference
" The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs."	( Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions. Buchmann, S; de Kanter, R; Delahaye, S; Gnerre, C; Kohl, C; Segrestaa, J; Sidharta, PN; Treiber, A, 2016)	0.43
"5% without dose-response relationship."	( Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet. Burnier, M; Dingemanse, J; Flamion, B; Gueneau de Mussy, P; Guérard, N; Iglarz, M; Maillard, MP; Sidharta, PN; Wuerzner, G, 2021)	0.62
" Phase 2 trial data support a significant reduction in blood pressure compared to placebo and similar blood pressure reduction compared to a moderately dosed angiotensin-converting enzyme inhibitor in patients with essential hypertension."	( Aprocitentan (a Dual Endothelin-Receptor Antagonist) for Treatment-Resistant Hypertension. Lisenby, KM; McCoy, EK, 2021)	0.62

Role	Description
antihypertensive agent	Any drug used in the treatment of acute or chronic vascular hypertension regardless of pharmacological mechanism.
endothelin receptor antagonist	A hormone antagonist that blocks endothelin receptors.
drug metabolite	null
xenobiotic metabolite	Any metabolite produced by metabolism of a xenobiotic compound.
[role information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Class	Description
aromatic ether	Any ether in which the oxygen is attached to at least one aryl substituent.
organobromine compound	A compound containing at least one carbon-bromine bond.
pyrimidines	Any compound having a pyrimidine as part of its structure.
sulfamides	Compounds where two amino groups are bound to an SO2 unit.
[compound class information is derived from Chemical Entities of Biological Interest (ChEBI), Hastings J, Owen G, Dekker A, Ennis M, Kale N, Muthukrishnan V, Turner S, Swainston N, Mendes P, Steinbeck C. (2016). ChEBI in 2016: Improved services and an expanding collection of metabolites. Nucleic Acids Res]

Protein Targets (9)

Potency Measurements

Protein	Taxonomy	Measurement	Average (µ)	Min (ref.)	Avg (ref.)	Max (ref.)	Bioassay(s)
cytochrome P450 family 3 subfamily A polypeptide 4	Homo sapiens (human)	Potency	7.5637	0.0123	7.9835	43.2770	AID1645841
G	Vesicular stomatitis virus	Potency	4.7724	0.0123	8.9648	39.8107	AID1645842
Interferon beta	Homo sapiens (human)	Potency	4.7724	0.0033	9.1582	39.8107	AID1645842
HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)	Potency	4.7724	0.0123	8.9648	39.8107	AID1645842
Inositol hexakisphosphate kinase 1	Homo sapiens (human)	Potency	4.7724	0.0123	8.9648	39.8107	AID1645842
cytochrome P450 2C9, partial	Homo sapiens (human)	Potency	4.7724	0.0123	8.9648	39.8107	AID1645842
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Inhibition Measurements

Protein	Taxonomy	Measurement	Average	Min (ref.)	Avg (ref.)	Max (ref.)	Bioassay(s)
Endothelin receptor type B	Rattus norvegicus (Norway rat)	IC50 (µMol)	0.9870	0.0000	1.1744	4.4000	AID1626382
Endothelin receptor type B	Homo sapiens (human)	IC50 (µMol)	0.9870	0.0001	0.6565	9.8000	AID1626382; AID699136
Endothelin-1 receptor	Homo sapiens (human)	IC50 (µMol)	0.0034	0.0000	0.7647	9.9000	AID1626381; AID699137
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (153)

Process	via Protein(s)	Taxonomy
cell surface receptor signaling pathway via JAK-STAT	Interferon beta	Homo sapiens (human)
response to exogenous dsRNA	Interferon beta	Homo sapiens (human)
B cell activation involved in immune response	Interferon beta	Homo sapiens (human)
cell surface receptor signaling pathway	Interferon beta	Homo sapiens (human)
cell surface receptor signaling pathway via JAK-STAT	Interferon beta	Homo sapiens (human)
response to virus	Interferon beta	Homo sapiens (human)
positive regulation of autophagy	Interferon beta	Homo sapiens (human)
cytokine-mediated signaling pathway	Interferon beta	Homo sapiens (human)
natural killer cell activation	Interferon beta	Homo sapiens (human)
positive regulation of peptidyl-serine phosphorylation of STAT protein	Interferon beta	Homo sapiens (human)
cellular response to interferon-beta	Interferon beta	Homo sapiens (human)
B cell proliferation	Interferon beta	Homo sapiens (human)
negative regulation of viral genome replication	Interferon beta	Homo sapiens (human)
innate immune response	Interferon beta	Homo sapiens (human)
positive regulation of innate immune response	Interferon beta	Homo sapiens (human)
regulation of MHC class I biosynthetic process	Interferon beta	Homo sapiens (human)
negative regulation of T cell differentiation	Interferon beta	Homo sapiens (human)
positive regulation of transcription by RNA polymerase II	Interferon beta	Homo sapiens (human)
defense response to virus	Interferon beta	Homo sapiens (human)
type I interferon-mediated signaling pathway	Interferon beta	Homo sapiens (human)
neuron cellular homeostasis	Interferon beta	Homo sapiens (human)
cellular response to exogenous dsRNA	Interferon beta	Homo sapiens (human)
cellular response to virus	Interferon beta	Homo sapiens (human)
negative regulation of Lewy body formation	Interferon beta	Homo sapiens (human)
negative regulation of T-helper 2 cell cytokine production	Interferon beta	Homo sapiens (human)
positive regulation of apoptotic signaling pathway	Interferon beta	Homo sapiens (human)
response to exogenous dsRNA	Interferon beta	Homo sapiens (human)
B cell differentiation	Interferon beta	Homo sapiens (human)
natural killer cell activation involved in immune response	Interferon beta	Homo sapiens (human)
adaptive immune response	Interferon beta	Homo sapiens (human)
T cell activation involved in immune response	Interferon beta	Homo sapiens (human)
humoral immune response	Interferon beta	Homo sapiens (human)
positive regulation of T cell mediated cytotoxicity	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
adaptive immune response	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
regulation of T cell anergy	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
defense response	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
immune response	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
detection of bacterium	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
regulation of interleukin-12 production	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
regulation of interleukin-6 production	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
protection from natural killer cell mediated cytotoxicity	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
innate immune response	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
regulation of dendritic cell differentiation	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
antigen processing and presentation of endogenous peptide antigen via MHC class Ib	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
negative regulation of transcription by RNA polymerase II	Endothelin receptor type B	Homo sapiens (human)
neural crest cell migration	Endothelin receptor type B	Homo sapiens (human)
positive regulation of protein phosphorylation	Endothelin receptor type B	Homo sapiens (human)
renin secretion into blood stream	Endothelin receptor type B	Homo sapiens (human)
regulation of heart rate	Endothelin receptor type B	Homo sapiens (human)
regulation of pH	Endothelin receptor type B	Homo sapiens (human)
cell surface receptor signaling pathway	Endothelin receptor type B	Homo sapiens (human)
negative regulation of adenylate cyclase activity	Endothelin receptor type B	Homo sapiens (human)
phospholipase C-activating G protein-coupled receptor signaling pathway	Endothelin receptor type B	Homo sapiens (human)
positive regulation of cytosolic calcium ion concentration	Endothelin receptor type B	Homo sapiens (human)
nervous system development	Endothelin receptor type B	Homo sapiens (human)
peripheral nervous system development	Endothelin receptor type B	Homo sapiens (human)
posterior midgut development	Endothelin receptor type B	Homo sapiens (human)
positive regulation of cell population proliferation	Endothelin receptor type B	Homo sapiens (human)
gene expression	Endothelin receptor type B	Homo sapiens (human)
negative regulation of neuron maturation	Endothelin receptor type B	Homo sapiens (human)
response to organic cyclic compound	Endothelin receptor type B	Homo sapiens (human)
vein smooth muscle contraction	Endothelin receptor type B	Homo sapiens (human)
calcium-mediated signaling	Endothelin receptor type B	Homo sapiens (human)
cGMP-mediated signaling	Endothelin receptor type B	Homo sapiens (human)
heparin metabolic process	Endothelin receptor type B	Homo sapiens (human)
melanocyte differentiation	Endothelin receptor type B	Homo sapiens (human)
regulation of fever generation	Endothelin receptor type B	Homo sapiens (human)
aldosterone metabolic process	Endothelin receptor type B	Homo sapiens (human)
enteric smooth muscle cell differentiation	Endothelin receptor type B	Homo sapiens (human)
positive regulation of urine volume	Endothelin receptor type B	Homo sapiens (human)
renal sodium excretion	Endothelin receptor type B	Homo sapiens (human)
epithelial fluid transport	Endothelin receptor type B	Homo sapiens (human)
vasoconstriction	Endothelin receptor type B	Homo sapiens (human)
vasodilation	Endothelin receptor type B	Homo sapiens (human)
negative regulation of apoptotic process	Endothelin receptor type B	Homo sapiens (human)
positive regulation of canonical NF-kappaB signal transduction	Endothelin receptor type B	Homo sapiens (human)
macrophage chemotaxis	Endothelin receptor type B	Homo sapiens (human)
response to pain	Endothelin receptor type B	Homo sapiens (human)
enteric nervous system development	Endothelin receptor type B	Homo sapiens (human)
regulation of epithelial cell proliferation	Endothelin receptor type B	Homo sapiens (human)
negative regulation of protein metabolic process	Endothelin receptor type B	Homo sapiens (human)
canonical Wnt signaling pathway	Endothelin receptor type B	Homo sapiens (human)
positive regulation of penile erection	Endothelin receptor type B	Homo sapiens (human)
establishment of endothelial barrier	Endothelin receptor type B	Homo sapiens (human)
renal sodium ion absorption	Endothelin receptor type B	Homo sapiens (human)
calcium ion transmembrane transport	Endothelin receptor type B	Homo sapiens (human)
cellular response to lipopolysaccharide	Endothelin receptor type B	Homo sapiens (human)
protein transmembrane transport	Endothelin receptor type B	Homo sapiens (human)
podocyte differentiation	Endothelin receptor type B	Homo sapiens (human)
endothelin receptor signaling pathway	Endothelin receptor type B	Homo sapiens (human)
renal albumin absorption	Endothelin receptor type B	Homo sapiens (human)
neuroblast migration	Endothelin receptor type B	Homo sapiens (human)
chordate pharynx development	Endothelin receptor type B	Homo sapiens (human)
response to sodium phosphate	Endothelin receptor type B	Homo sapiens (human)
response to endothelin	Endothelin receptor type B	Homo sapiens (human)
developmental pigmentation	Endothelin receptor type B	Homo sapiens (human)
mitotic cell cycle	Endothelin-1 receptor	Homo sapiens (human)
branching involved in blood vessel morphogenesis	Endothelin-1 receptor	Homo sapiens (human)
response to hypoxia	Endothelin-1 receptor	Homo sapiens (human)
in utero embryonic development	Endothelin-1 receptor	Homo sapiens (human)
blood vessel remodeling	Endothelin-1 receptor	Homo sapiens (human)
response to amphetamine	Endothelin-1 receptor	Homo sapiens (human)
regulation of heart rate	Endothelin-1 receptor	Homo sapiens (human)
glomerular filtration	Endothelin-1 receptor	Homo sapiens (human)
cardiac chamber formation	Endothelin-1 receptor	Homo sapiens (human)
left ventricular cardiac muscle tissue morphogenesis	Endothelin-1 receptor	Homo sapiens (human)
atrial cardiac muscle tissue development	Endothelin-1 receptor	Homo sapiens (human)
cardiac neural crest cell migration involved in outflow tract morphogenesis	Endothelin-1 receptor	Homo sapiens (human)
noradrenergic neuron differentiation	Endothelin-1 receptor	Homo sapiens (human)
intracellular calcium ion homeostasis	Endothelin-1 receptor	Homo sapiens (human)
smooth muscle contraction	Endothelin-1 receptor	Homo sapiens (human)
mitochondrion organization	Endothelin-1 receptor	Homo sapiens (human)
signal transduction	Endothelin-1 receptor	Homo sapiens (human)
G protein-coupled receptor signaling pathway	Endothelin-1 receptor	Homo sapiens (human)
activation of adenylate cyclase activity	Endothelin-1 receptor	Homo sapiens (human)
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	Endothelin-1 receptor	Homo sapiens (human)
phospholipase C-activating G protein-coupled receptor signaling pathway	Endothelin-1 receptor	Homo sapiens (human)
positive regulation of cytosolic calcium ion concentration	Endothelin-1 receptor	Homo sapiens (human)
respiratory gaseous exchange by respiratory system	Endothelin-1 receptor	Homo sapiens (human)
regulation of blood pressure	Endothelin-1 receptor	Homo sapiens (human)
cell population proliferation	Endothelin-1 receptor	Homo sapiens (human)
response to wounding	Endothelin-1 receptor	Homo sapiens (human)
gene expression	Endothelin-1 receptor	Homo sapiens (human)
protein kinase A signaling	Endothelin-1 receptor	Homo sapiens (human)
regulation of glucose transmembrane transport	Endothelin-1 receptor	Homo sapiens (human)
neural crest cell fate commitment	Endothelin-1 receptor	Homo sapiens (human)
artery smooth muscle contraction	Endothelin-1 receptor	Homo sapiens (human)
neuron remodeling	Endothelin-1 receptor	Homo sapiens (human)
heparin metabolic process	Endothelin-1 receptor	Homo sapiens (human)
thyroid gland development	Endothelin-1 receptor	Homo sapiens (human)
cellular response to oxidative stress	Endothelin-1 receptor	Homo sapiens (human)
embryonic heart tube development	Endothelin-1 receptor	Homo sapiens (human)
aorta development	Endothelin-1 receptor	Homo sapiens (human)
vasoconstriction	Endothelin-1 receptor	Homo sapiens (human)
norepinephrine metabolic process	Endothelin-1 receptor	Homo sapiens (human)
middle ear morphogenesis	Endothelin-1 receptor	Homo sapiens (human)
positive regulation of canonical NF-kappaB signal transduction	Endothelin-1 receptor	Homo sapiens (human)
cellular response to human chorionic gonadotropin stimulus	Endothelin-1 receptor	Homo sapiens (human)
enteric nervous system development	Endothelin-1 receptor	Homo sapiens (human)
sympathetic nervous system development	Endothelin-1 receptor	Homo sapiens (human)
axon extension	Endothelin-1 receptor	Homo sapiens (human)
embryonic skeletal system development	Endothelin-1 receptor	Homo sapiens (human)
neuromuscular process	Endothelin-1 receptor	Homo sapiens (human)
sodium ion homeostasis	Endothelin-1 receptor	Homo sapiens (human)
canonical Wnt signaling pathway	Endothelin-1 receptor	Homo sapiens (human)
face development	Endothelin-1 receptor	Homo sapiens (human)
axonogenesis involved in innervation	Endothelin-1 receptor	Homo sapiens (human)
establishment of endothelial barrier	Endothelin-1 receptor	Homo sapiens (human)
pharyngeal arch artery morphogenesis	Endothelin-1 receptor	Homo sapiens (human)
renal sodium ion absorption	Endothelin-1 receptor	Homo sapiens (human)
calcium ion transmembrane transport	Endothelin-1 receptor	Homo sapiens (human)
cellular response to follicle-stimulating hormone stimulus	Endothelin-1 receptor	Homo sapiens (human)
cellular response to luteinizing hormone stimulus	Endothelin-1 receptor	Homo sapiens (human)
protein transmembrane transport	Endothelin-1 receptor	Homo sapiens (human)
glomerular endothelium development	Endothelin-1 receptor	Homo sapiens (human)
podocyte differentiation	Endothelin-1 receptor	Homo sapiens (human)
endothelin receptor signaling pathway involved in heart process	Endothelin-1 receptor	Homo sapiens (human)
renal albumin absorption	Endothelin-1 receptor	Homo sapiens (human)
vascular associated smooth muscle cell development	Endothelin-1 receptor	Homo sapiens (human)
mesenchymal cell apoptotic process	Endothelin-1 receptor	Homo sapiens (human)
sympathetic neuron axon guidance	Endothelin-1 receptor	Homo sapiens (human)
semaphorin-plexin signaling pathway involved in axon guidance	Endothelin-1 receptor	Homo sapiens (human)
podocyte apoptotic process	Endothelin-1 receptor	Homo sapiens (human)
meiotic cell cycle process involved in oocyte maturation	Endothelin-1 receptor	Homo sapiens (human)
cranial skeletal system development	Endothelin-1 receptor	Homo sapiens (human)
response to acetylcholine	Endothelin-1 receptor	Homo sapiens (human)
regulation of protein localization to cell leading edge	Endothelin-1 receptor	Homo sapiens (human)
positive regulation of cation channel activity	Endothelin-1 receptor	Homo sapiens (human)
endothelin receptor signaling pathway	Endothelin-1 receptor	Homo sapiens (human)
developmental pigmentation	Endothelin-1 receptor	Homo sapiens (human)
inositol phosphate metabolic process	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
phosphatidylinositol phosphate biosynthetic process	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
negative regulation of cold-induced thermogenesis	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol phosphate biosynthetic process	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (22)

Process	via Protein(s)	Taxonomy
cytokine activity	Interferon beta	Homo sapiens (human)
cytokine receptor binding	Interferon beta	Homo sapiens (human)
type I interferon receptor binding	Interferon beta	Homo sapiens (human)
protein binding	Interferon beta	Homo sapiens (human)
chloramphenicol O-acetyltransferase activity	Interferon beta	Homo sapiens (human)
TAP binding	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
signaling receptor binding	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
protein binding	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
peptide antigen binding	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
TAP binding	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
protein-folding chaperone binding	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
endothelin receptor activity	Endothelin receptor type B	Homo sapiens (human)
protein binding	Endothelin receptor type B	Homo sapiens (human)
peptide hormone binding	Endothelin receptor type B	Homo sapiens (human)
type 1 angiotensin receptor binding	Endothelin receptor type B	Homo sapiens (human)
phosphatidylinositol phospholipase C activity	Endothelin-1 receptor	Homo sapiens (human)
endothelin receptor activity	Endothelin-1 receptor	Homo sapiens (human)
protein binding	Endothelin-1 receptor	Homo sapiens (human)
inositol-1,3,4,5,6-pentakisphosphate kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol hexakisphosphate kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol heptakisphosphate kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol hexakisphosphate 5-kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
protein binding	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
ATP binding	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol hexakisphosphate 1-kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol hexakisphosphate 3-kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol 5-diphosphate pentakisphosphate 5-kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
inositol diphosphate tetrakisphosphate kinase activity	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (23)

Process	via Protein(s)	Taxonomy
extracellular space	Interferon beta	Homo sapiens (human)
extracellular region	Interferon beta	Homo sapiens (human)
Golgi membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
endoplasmic reticulum	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
Golgi apparatus	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
plasma membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
cell surface	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
ER to Golgi transport vesicle membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
secretory granule membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
phagocytic vesicle membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
early endosome membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
recycling endosome membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
extracellular exosome	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
lumenal side of endoplasmic reticulum membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
MHC class I protein complex	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
extracellular space	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
external side of plasma membrane	HLA class I histocompatibility antigen, B alpha chain	Homo sapiens (human)
plasma membrane	Endothelin receptor type B	Homo sapiens (human)
nuclear membrane	Endothelin receptor type B	Homo sapiens (human)
plasma membrane	Endothelin receptor type B	Homo sapiens (human)
plasma membrane	Endothelin-1 receptor	Homo sapiens (human)
plasma membrane	Endothelin-1 receptor	Homo sapiens (human)
fibrillar center	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
nucleoplasm	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
cytosol	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
nucleus	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
cytoplasm	Inositol hexakisphosphate kinase 1	Homo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (9)

Assay ID	Title	Year	Journal	Article
AID1296008	Cytotoxic Profiling of Annotated Libraries Using Quantitative High-Throughput Screening	2020	SLAS discovery : advancing life sciences R & D, 01, Volume: 25, Issue:1	Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening.
AID1347159	Primary screen GU Rhodamine qHTS for Zika virus inhibitors: Unlinked NS2B-NS3 protease assay	2020	Proceedings of the National Academy of Sciences of the United States of America, 12-08, Volume: 117, Issue:49	Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors.
AID1346987	P-glycoprotein substrates identified in KB-8-5-11 adenocarcinoma cell line, qHTS therapeutic library screen	2019	Molecular pharmacology, 11, Volume: 96, Issue:5	A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein.
AID1346986	P-glycoprotein substrates identified in KB-3-1 adenocarcinoma cell line, qHTS therapeutic library screen	2019	Molecular pharmacology, 11, Volume: 96, Issue:5	A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein.
AID1347160	Primary screen NINDS Rhodamine qHTS for Zika virus inhibitors	2020	Proceedings of the National Academy of Sciences of the United States of America, 12-08, Volume: 117, Issue:49	Therapeutic candidates for the Zika virus identified by a high-throughput screen for Zika protease inhibitors.
AID1626382	Displacement of [125I]-ET-1 from human ETB receptor expressed in CHO cell membranes after 2 hrs by scintillation counting	2016	Bioorganic & medicinal chemistry letters, 08-01, Volume: 26, Issue:15	From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.
AID1626381	Displacement of [125I]-ET-1 from human ETA receptor expressed in CHO cell membranes after 2 hrs by scintillation counting	2016	Bioorganic & medicinal chemistry letters, 08-01, Volume: 26, Issue:15	From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.
AID699136	Displacement of [I125]ET1 from recombinant ETB receptor expressed in CHO cells after 2 hrs by TopCount analysis	2012	Journal of medicinal chemistry, Sep-13, Volume: 55, Issue:17	The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist.
AID699137	Displacement of [I125]ET1 from recombinant ETA receptor expressed in CHO cells after 2 hrs by TopCount analysis	2012	Journal of medicinal chemistry, Sep-13, Volume: 55, Issue:17	The discovery of N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide (Macitentan), an orally active, potent dual endothelin receptor antagonist.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Timeframe	Studies, This Drug (%)	All Drugs %
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	0 (0.00)	29.6817
2010's	14 (46.67)	24.3611
2020's	16 (53.33)	2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Publication Type	This drug (%)	All Drugs (%)
Trials	16 (53.33%)	5.53%
Reviews	6 (20.00%)	6.00%
Case Studies	0 (0.00%)	4.05%
Observational	0 (0.00%)	0.25%
Other	8 (26.67%)	84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Substance	Relationship Strength	Studies	Trials	Classes	Roles
uric acid Uric Acid: An oxidation product, via XANTHINE OXIDASE, of oxypurines such as XANTHINE and HYPOXANTHINE. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals URATE OXIDASE further oxidizes it to ALLANTOIN.. uric acid : An oxopurine that is the final oxidation product of purine metabolism.. 6-hydroxy-1H-purine-2,8(7H,9H)-dione : A tautomer of uric acid having oxo groups at C-2 and C-8 and a hydroxy group at C-6.. 7,9-dihydro-1H-purine-2,6,8(3H)-trione : An oxopurine in which the purine ring is substituted by oxo groups at positions 2, 6, and 8.	5.55	2	2	uric acid	Escherichia coli metabolite; human metabolite; mouse metabolite
ketoconazole 1-acetyl-4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine : A dioxolane that is 1,3-dioxolane which is substituted at positions 2, 2, and 4 by imidazol-1-ylmethyl, 2,4-dichlorophenyl, and [para-(4-acetylpiperazin-1-yl)phenoxy]methyl groups, respectively.	3.89	2	1	dichlorobenzene; dioxolane; ether; imidazoles; N-acylpiperazine; N-arylpiperazine
sulfamethoxazole Sulfamethoxazole: A bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. Its broad spectrum of activity has been limited by the development of resistance. (From Martindale, The Extra Pharmacopoeia, 30th ed, p208). sulfamethoxazole : An isoxazole (1,2-oxazole) compound having a methyl substituent at the 5-position and a 4-aminobenzenesulfonamido group at the 3-position.	3.23	1	0	isoxazoles; substituted aniline; sulfonamide antibiotic; sulfonamide	antibacterial agent; antiinfective agent; antimicrobial agent; drug allergen; EC 1.1.1.153 [sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming)] inhibitor; EC 2.5.1.15 (dihydropteroate synthase) inhibitor; environmental contaminant; epitope; P450 inhibitor; xenobiotic
aldosterone [no description available]	3.7	1	1	11beta-hydroxy steroid; 18-oxo steroid; 20-oxo steroid; 21-hydroxy steroid; 3-oxo-Delta(4) steroid; C21-steroid hormone; mineralocorticoid; primary alpha-hydroxy ketone; steroid aldehyde	human metabolite; mouse metabolite
bosentan anhydrous Bosentan: A sulfonamide and pyrimidine derivative that acts as a dual endothelin receptor antagonist used to manage PULMONARY HYPERTENSION and SYSTEMIC SCLEROSIS.	5.5	4	1	primary alcohol; pyrimidines; sulfonamide	antihypertensive agent; endothelin receptor antagonist
ro 46-2005 Ro 46-2005: an orally active non-peptide antagonist of endothelin receptors; structure given in first source	3.23	1	0
tezosentan tezosentan: structure in first source	3.23	1	0
lu 135252 [no description available]	3.23	1	0
tbc-11251 sitaxsentan: endothelin A receptor antagonist; structure in first source	3.23	1	0	benzodioxoles
bq 123 cyclo(Trp-Asp-Pro-Val-Leu): derived from the modification of a natural lead of BE-18257B, an endothelin A receptor antagonist; has neuroprotective activity; amino acid sequence given in first source	2.07	1	0	cyclic peptide
ro 46-8443 Ro 46-8443: a non-peptide endothelin ET(B) receptor selective antagonist; structure given in first source	3.23	1	0
ro 47-8634 Ro 47-8634: structure in first source	3.23	1	0
clazosentan clazosentan: endothelin A receptor antagonist used for cerebral vasospasm; structure in first source;	3.23	1	0
lu 208075 ambrisentan: an ET(A) receptor antagonist and antihypertensive agent; studied for use in pulmonary arterial hypertension	3.23	1	0	diarylmethane
bms 193884 [no description available]	3.23	1	0
zibotentan ZD4054: a potent endothelin receptor A antagonist that inhibits ovarian carcinoma cell proliferation	3.23	1	0	phenylpyridine
avosentan Avosentan: structure in first source	3.23	1	0
macitentan [no description available]	9.84	14	8	aromatic ether; organobromine compound; pyrimidines; ring assembly; sulfamides	antihypertensive agent; endothelin receptor antagonist; orphan drug
endothelin-1 Endothelin-1: A 21-amino acid peptide produced in a variety of tissues including endothelial and vascular smooth-muscle cells, neurons and astrocytes in the central nervous system, and endometrial cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production. (N Eng J Med 1995;333(6):356-63)	4.51	2	0
warfarin Warfarin: An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide.. warfarin : A racemate comprising equal amounts of (R)- and (S)-warfarin. Extensively used as both an anticoagulant drug and as a pesticide against rats and mice.. 4-hydroxy-3-(3-oxo-1-phenylbutyl)-1-benzopyran-2-one : A member of the class of coumarins that is 4-hydroxycoumarin which is substituted at position 3 by a 1-phenyl-3-oxo-1-butyl group.	2.13	1	0	benzenes; hydroxycoumarin; methyl ketone
cyclosporine Cyclosporine: A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).	3.89	2	1
rifampin Rifampin: A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)	3.89	2	1	cyclic ketal; hydrazone; N-iminopiperazine; N-methylpiperazine; rifamycins; semisynthetic derivative; zwitterion	angiogenesis inhibitor; antiamoebic agent; antineoplastic agent; antitubercular agent; DNA synthesis inhibitor; EC 2.7.7.6 (RNA polymerase) inhibitor; Escherichia coli metabolite; geroprotector; leprostatic drug; neuroprotective agent; pregnane X receptor agonist; protein synthesis inhibitor
sildenafil citrate Sildenafil Citrate: A PHOSPHODIESTERASE TYPE-5 INHIBITOR; VASODILATOR AGENT and UROLOGICAL AGENT that is used in the treatment of ERECTILE DYSFUNCTION and PRIMARY PULMONARY HYPERTENSION.. sildenafil citrate : The citrate salt of sildenafil.	2.13	1	0	citrate salt	EC 3.1.4.35 (3',5'-cyclic-GMP phosphodiesterase) inhibitor; vasodilator agent
vardenafil dihydrochloride Vardenafil Dihydrochloride: A piperazine derivative, PHOSPHODIESTERASE 5 INHIBITOR and VASODILATOR AGENT that is used as a UROLOGICAL AGENT in the treatment of ERECTILE DYSFUNCTION.	2.21	1	0

Condition	Indicated	Relationship Strength	Studies	Trials
Congenital Zika Syndrome [description not available]	0	2.25	1	0
Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	0	2.25	1	0
Zika Virus Infection A viral disease transmitted by the bite of AEDES mosquitoes infected with ZIKA VIRUS. Its mild DENGUE-like symptoms include fever, rash, headaches and ARTHRALGIA. The viral infection during pregnancy, in rare cases, is associated with congenital brain and ocular abnormalities, called Congenital Zika Syndrome, including MICROCEPHALY and may also lead to GUILLAIN-BARRE SYNDROME.	0	2.25	1	0
Blood Pressure, High [description not available]	0	10.7	10	5
Hypertension Persistently high systemic arterial BLOOD PRESSURE. Based on multiple readings (BLOOD PRESSURE DETERMINATION), hypertension is currently defined as when SYSTOLIC PRESSURE is consistently greater than 140 mm Hg or when DIASTOLIC PRESSURE is consistently 90 mm Hg or more.	1	12.7	10	5
Liver Dysfunction [description not available]	0	4.72	1	1
Liver Diseases Pathological processes of the LIVER.	1	6.72	1	1
Weight Gain Increase in BODY WEIGHT over existing weight.	0	3.7	1	1
Pulmonary Arterial Hypertension A progressive rare pulmonary disease characterized by high blood pressure in the PULMONARY ARTERY.	0	2.66	2	0
Heritable Pulmonary Arterial Hypertension [description not available]	0	3.53	1	1
Familial Primary Pulmonary Hypertension Familial or idiopathic hypertension in the PULMONARY CIRCULATION which is not secondary to other disease.	0	3.53	1	1
Pulmonary Hypertension [description not available]	0	7.6	4	4
Hypertension, Pulmonary Increased VASCULAR RESISTANCE in the PULMONARY CIRCULATION, usually secondary to HEART DISEASES or LUNG DISEASES.	0	7.6	4	4
Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms.	0	3.59	1	1
Sclerosis, Systemic [description not available]	0	2.11	1	0
Scleroderma, Systemic A chronic multi-system disorder of CONNECTIVE TISSUE. It is characterized by SCLEROSIS in the SKIN, the LUNGS, the HEART, the GASTROINTESTINAL TRACT, the KIDNEYS, and the MUSCULOSKELETAL SYSTEM. Other important features include diseased small BLOOD VESSELS and AUTOANTIBODIES. The disorder is named for its most prominent feature (hard skin), and classified into subsets by the extent of skin thickening: LIMITED SCLERODERMA and DIFFUSE SCLERODERMA.	0	2.11	1	0

act-132577

Description

Cross-References

Synonyms (44)

Research Excerpts

Toxicity

Pharmacokinetics

Compound-Compound Interactions

Bioavailability

Dosage Studied

Roles (4)

Drug Classes (4)

Protein Targets (9)

Potency Measurements

Inhibition Measurements

Biological Processes (153)

Molecular Functions (22)

Ceullar Components (23)

Bioassays (9)

Research

Studies (30)

Market Indicators

Research Demand Index: 20.16

Study Types

act-132577

Description

Cross-References

Synonyms (44)

Research Excerpts

Toxicity

Pharmacokinetics

Compound-Compound Interactions

Bioavailability

Dosage Studied

Roles (4)

Drug Classes (4)

Protein Targets (9)

Potency Measurements

Inhibition Measurements

Biological Processes (153)

Molecular Functions (22)

Ceullar Components (23)

Bioassays (9)

Research

Studies (30)

Market Indicators

Research Demand Index: 20.16

Study Types

Related Drugs (24)

Related Conditions (16)