Target Information

Target General Information

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Target ID

T99954 (Former ID: TTDS00170)

Target Name

Prostacyclin receptor (PTGIR)

Synonyms

Prostanoid IP receptor; Prostaglandin I2 receptor; PRIPR; PGI2 receptor; PGI receptor; IP prostanoid receptor

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Gene Name

PTGIR

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Abortion [ICD-11: JA00]

Pulmonary hypertension [ICD-11: BB01]

Coronary atherosclerosis [ICD-11: BA80]

Function

The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase. Receptor for prostacyclin (prostaglandin I2 or PGI2).

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BioChemical Class

GPCR rhodopsin

UniProt ID

PI2R_HUMAN

Sequence

MADSCRNLTYVRGSVGPATSTLMFVAGVVGNGLALGILSARRPARPSAFAVLVTGLAATD
LLGTSFLSPAVFVAYARNSSLLGLARGGPALCDAFAFAMTFFGLASMLILFAMAVERCLA
LSHPYLYAQLDGPRCARLALPAIYAFCVLFCALPLLGLGQHQQYCPGSWCFLRMRWAQPG
GAAFSLAYAGLVALLVAAIFLCNGSVTLSLCRMYRQQKRHQGSLGPRPRTGEDEVDHLIL
LALMTVVMAVCSLPLTIRCFTQAVAPDSSSEMGDLLAFRFYAFNPILDPWVFILFRKAVF
QRLKLWVCCLCLGPAHGDSQTPLSQLASGRRDPRAPSAPVGKEGSCVPLSAWGEGQVEPL
PPTQQSSGSAVGTSSKAEASVACSLC

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 7 Approved Drugs

Dinoprost Tromethamine

Drug Info

Approved

Abortion

[2]

Epoprostenol

Drug Info

Approved

Pulmonary hypertension

[3], [4]

Misoprostol

Drug Info

Approved

Medical abortion

[5], [6]

Selexipag

Drug Info

Approved

Pulmonary arterial hypertension

[7], [8]

Treprostinil

Drug Info

Approved

Pulmonary arterial hypertension

[4], [9]

Beraprost

Drug Info

Phase 4

Pulmonary hypertension

[10]

LAROPIPRANT

Drug Info

Phase 4

Coronary heart disease

[11]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

esuberaprost

Drug Info

Phase 3

Gout

[12]

Ralinepag

Drug Info

Phase 2

Pulmonary hypertension

[13]

Discontinued Drug(s)

[+] 5 Discontinued Drugs

Clinprost

Drug Info

Discontinued in Preregistration

Asthma

[14]

Ataprost

Drug Info

Discontinued in Phase 3

Asthma

[15]

YM533

Drug Info

Discontinued in Phase 3

Chronic renal failure

[16]

OP-2507

Drug Info

Discontinued in Phase 2

Hypertension

[17]

EPTALOPROST

Drug Info

Terminated

Solid tumour/cancer

[18]

Mode of Action

[+] 4 Modes of Action

Antagonist

[+] 5 Antagonist drugs

Dinoprost Tromethamine

Drug Info

[1], [19]

Misoprostol

Drug Info

[1], [23], [24]

BAY-73-1449

Drug Info

[38]

RO1138452

Drug Info

[45]

RO3244794

Drug Info

[45]

Agonist

[+] 15 Agonist drugs

Epoprostenol

Drug Info

[20], [21], [22]

Selexipag

Drug Info

[25]

Treprostinil

Drug Info

[26]

Beraprost

Drug Info

[27]

esuberaprost

Drug Info

[12]

Ralinepag

Drug Info

[29]

AFP-07

Drug Info

[37]

BMY 45778

Drug Info

[39]

butaprost (free acid form)

Drug Info

[40]

carbacyclin

Drug Info

[40]

cicaprost

Drug Info

[41]

EP 157

Drug Info

[42]

isocarbacyclin

Drug Info

[41]

TEI-9063

Drug Info

[39]

U46619

Drug Info

[40]

Inhibitor

[+] 4 Inhibitor drugs

LAROPIPRANT

Drug Info

[28]

AP-227

Drug Info

[34]

FR-181157

Drug Info

[43]

FR-193262

Drug Info

[44]

Modulator

[+] 6 Modulator drugs

Clinprost

Drug Info

[30]

Ataprost

Drug Info

[31]

YM533

Drug Info

[32]

OP-2507

Drug Info

[33]

EPTALOPROST

Drug Info

[35], [36]

Prostacyclin analog

Drug Info

[32]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 2AG2 (OR2AG2)	PF13853	33.898 (40/118)	2.50E-04
Olfactory receptor 1L3 (OR1L3)	PF13853	25.926 (35/135)	7.28E-04
Olfactory receptor 4K13 (OR4K13)	PF13853	27.193 (31/114)	7.49E-04
Olfactory receptor 4C6 (OR4C6)	PF13853	27.869 (34/122)	1.00E-03
Olfactory receptor 4K14 (OR4K14)	PF13853	30.252 (36/119)	3.00E-03
Olfactory receptor 5P3 (OR5P3)	PF13853	22.840 (37/162)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Vascular smooth muscle contraction	hsa04270	Affiliated Target
Class: Organismal Systems => Circulatory system	Pathway Hierarchy
Platelet activation	hsa04611	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	2	Degree centrality	2.15E-04	Betweenness centrality	2.88E-05
Closeness centrality	1.83E-01	Radiality	1.31E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	2.55E+01	Topological coefficient	5.00E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Neuroactive ligand-receptor interaction

Vascular smooth muscle contraction

Platelet activation

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Intracellular Signalling Through Prostacyclin Receptor and Prostacyclin

PID Pathway

[+] 1 PID Pathways

Thromboxane A2 receptor signaling

Reactome

[+] 2 Reactome Pathways

Prostanoid ligand receptors

G alpha (s) signalling events

WikiPathways

[+] 7 WikiPathways

Prostaglandin Synthesis and Regulation

GPCRs, Class A Rhodopsin-like

Small Ligand GPCRs

Endothelin Pathways

Platelet homeostasis

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

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REF 1

Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J Biol Chem. 2003 Feb 28;278(9):6947-58.

REF 2

Drug information of Dinoprost Tromethamine, 2008. eduDrugs.

REF 3

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1915).

REF 4

Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.

REF 5

REF 6

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 7

REF 8

ClinicalTrials.gov (NCT01106014) Selexipag (ACT-293987) in Pulmonary Arterial Hypertension, GRIPHON Trial. U.S. National Institutes of Health.

REF 9

REF 10

ClinicalTrials.gov (NCT03431649) Efficacy of Beraprost in Lowering Pulmonary Arterial Pressure in Children. U.S. National Institutes of Health.

REF 11

ClinicalTrials.gov (NCT01126073) A Double Blind, Randomized Study to Compare Influence of Niacin/Laropiprant on Functional and Morphological Characteristics of Arterial Wall and Parameters of Inflammation in Subjects With Coronary Heart Disease Already Treated With a Statin in Miran Sebestjen, University Medical Centre Ljubljana.

REF 12

Specific binding of the new stable epoprostenol analogue beraprost sodium to prostacyclin receptors on human and rat platelets. Arzneimittelforschung. 1989 Apr;39(4):495-9.

REF 13

ClinicalTrials.gov (NCT02279745) Long Term Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension. U.S. National Institutes of Health.

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003132)

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002073)

REF 16

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026064)

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005417)

REF 18

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003249)

REF 19

Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the cardiovascular system. Circulation. 1994 Oct;90(4):1643-7.

REF 20

Novel signaling pathways promote a paracrine wave of prostacyclin-induced vascular smooth muscle differentiation. J Mol Cell Cardiol. 2009 May;46(5):682-94.

REF 21

Signaling through Gi family members in platelets. Redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem. 2002 Nov 29;277(48):46035-42.

REF 22

Expression of human hexosaminidase-A phenotype depends on genes assigned to chromosomes 5 and 15. Birth Defects Orig Artic Ser. 1976;12(7):192-6.

REF 23

The future potential of eicosanoids and their inhibitors in paediatric practice. Drugs. 1998 Aug;56(2):169-76.

REF 24

Structural organization and chromosomal assignment of the human prostacyclin receptor gene. Genomics. 1995 May 1;27(1):142-8.

REF 25

Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012 Oct;40(4):874-80.

REF 26

Dosing considerations in the use of intravenous prostanoids in pulmonary arterial hypertension: an experience-based review. Am Heart J. 2009 Apr;157(4):625-35.

REF 27

Prostaglandin I2 IP Receptor Agonist, Beraprost, Prevents Transient Global Cerebral Ischemia Induced Hippocampal CA1 Injury in Aging Mice. J Neurol Disord. 2014;2:1000174.

REF 28

Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydroc... J Med Chem. 2007 Feb 22;50(4):794-806.

REF 29

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 30

Protective effect of a prostaglandin I2 analog, TEI-7165, on ischemic neuronal damage in gerbils. Brain Res. 1997 Sep 26;769(2):321-8.

REF 31

Pharmacokinetics of intravenous ataprost alfadex, a new prostaglandin I2 analog in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1993 Aug;31(8):373-5.

REF 32

REF 33

Effect of a prostaglandin I(2) analog on the expression of thrombomodulin in liver and spleen endothelial cells after an extensive hepatectomy. Surg Today. 2011 Feb;41(2):230-6.

REF 34

Molecular design of novel PGI2 agonists without PG skeleton, Bioorg. Med. Chem. Lett. 5(10):1071-1076 (1995).

REF 35

Bioactivation of eptaloprost in animals and man. Prostaglandins. 1993 Aug;46(2):177-89.

REF 36

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 37

7,7-Difluoroprostacyclin derivative, AFP-07, a highly selective and potent agonist for the prostacyclin receptor. Prostaglandins. 1997 Feb;53(2):83-90.

REF 38

Vascular actions of the prostacyclin receptor antagonist BAY 73-1449 in the portal hypertensive rat. Eur J Pharmacol. 2008 Aug 20;590(1-3):322-6.

REF 39

Relaxant actions of nonprostanoid prostacyclin mimetics on human pulmonary artery. J Cardiovasc Pharmacol. 1997 Apr;29(4):525-35.

REF 40

The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta. 2000 Jan 17;1483(2):285-93.

REF 41

Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br J Pharmacol. 1997 Sep;122(2):217-24.

REF 42

Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics. Br J Pharmacol. 1986 Mar;87(3):543-51.

REF 43

Replacing the cyclohexene-linker of FR181157 leading to novel IP receptor agonists: orally active prostacyclin mimetics. Part 6. Bioorg Med Chem Lett. 2006 Sep 15;16(18):4861-4.

REF 44

Discovery of new diphenyloxazole derivatives containing a pyrrolidine ring: orally active prostacyclin mimetics. Part 2. Bioorg Med Chem Lett. 2005 Jul 1;15(13):3279-83.

REF 45

RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol. 2006 Feb;147(3):335-45.

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