Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTOFYT1)

• DTT Name: Prostacyclin receptor (PTGIR)
• Synonyms: Prostanoid IP receptor; Prostaglandin I2 receptor; PRIPR; PGI2 receptor; PGI receptor; IP prostanoid receptor
• Gene Name: PTGIR
• DTT Type: Successful target; [1]
• Related Disease:
  Abortion [ICD-11: JA00]
  Coronary atherosclerosis [ICD-11: BA80]
  Pulmonary hypertension [ICD-11: BB01]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: PI2R_HUMAN
• TTD ID: T99954
• Sequence:
  MADSCRNLTYVRGSVGPATSTLMFVAGVVGNGLALGILSARRPARPSAFAVLVTGLAATD
  LLGTSFLSPAVFVAYARNSSLLGLARGGPALCDAFAFAMTFFGLASMLILFAMAVERCLA
  LSHPYLYAQLDGPRCARLALPAIYAFCVLFCALPLLGLGQHQQYCPGSWCFLRMRWAQPG
  GAAFSLAYAGLVALLVAAIFLCNGSVTLSLCRMYRQQKRHQGSLGPRPRTGEDEVDHLIL
  LALMTVVMAVCSLPLTIRCFTQAVAPDSSSEMGDLLAFRFYAFNPILDPWVFILFRKAVF
  QRLKLWVCCLCLGPAHGDSQTPLSQLASGRRDPRAPSAPVGKEGSCVPLSAWGEGQVEPL
  PPTQQSSGSAVGTSSKAEASVACSLC
• Function: The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase. Receptor for prostacyclin (prostaglandin I2 or PGI2).
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Vascular smooth muscle contraction (hsa04270)
  Platelet activation (hsa04611)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Prostanoid ligand receptors (R-HSA-391908)

Molecular Interaction Atlas (MIA) of This DTT

7 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dinoprost Tromethamine	DMXQKSL	Abortion	JA00	Approved	[1], [2]
Epoprostenol	DMUTYR2	Pulmonary hypertension	BB01	Approved	[3], [4], [5]
Misoprostol	DMHVJFK	Medical abortion	JA00.1Z	Approved	[1], [6], [7]
Selexipag	DMAHSU0	Pulmonary arterial hypertension	BB01.0	Approved	[8]
Treprostinil	DMTIQF3	Pulmonary arterial hypertension	BB01.0	Approved	[9]
Beraprost	DMWL182	Pulmonary hypertension	BB01	Phase 4	[10]
LAROPIPRANT	DM5FABJ	Coronary heart disease	BA80.Z	Phase 4	[11]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
esuberaprost	DMXLGED	Gout	FA25	Phase 3	[12]
Ralinepag	DM7G4Y9	Pulmonary arterial hypertension	BB01.0	Phase 2	[13]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Clinprost	DM6E5VA	Asthma	CA23	Discontinued in Preregistration	[14]
Ataprost	DMPTG39	Asthma	CA23	Discontinued in Phase 3	[15]
YM533	DMFEN6T	Chronic renal failure	GB61.Z	Discontinued in Phase 3	[16]
OP-2507	DMQM4OV	Hypertension	BA00-BA04	Discontinued in Phase 2	[17]
AP-227	DM7LAXF	N. A.	N. A.	Terminated	[18]
EPTALOPROST	DM2NHLW	Solid tumour/cancer	2A00-2F9Z	Terminated	[19], [20]

15 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AFP-07	DM4WVMU	Discovery agent	N.A.	Investigative	[21]
BAY-73-1449	DM5CPJ2	Discovery agent	N.A.	Investigative	[22]
BMY 45778	DMT02B8	Discovery agent	N.A.	Investigative	[23]
butaprost (free acid form)	DM5MZHP	Discovery agent	N.A.	Investigative	[24]
carbacyclin	DMMBQYE	Discovery agent	N.A.	Investigative	[24]
cicaprost	DM7ZJ4H	Discovery agent	N.A.	Investigative	[25]
EP 157	DMSPIF2	Discovery agent	N.A.	Investigative	[26]
FR-181157	DM2V7U1	Discovery agent	N.A.	Investigative	[27]
FR-193262	DM9BS3W	Discovery agent	N.A.	Investigative	[28]
isocarbacyclin	DMZR7W6	Discovery agent	N.A.	Investigative	[25]
Prostacyclin analog	DMXCJ7O	Pulmonary hypertension	BB01	Investigative	[16]
RO1138452	DMAOI51	Discovery agent	N.A.	Investigative	[29]
RO3244794	DMBFCKD	Discovery agent	N.A.	Investigative	[29]
TEI-9063	DMGQLYR	Discovery agent	N.A.	Investigative	[23]
U46619	DM13FX4	Discovery agent	N.A.	Investigative	[24]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	7.12E-02	-0.13	-0.33

References

• [1] Palmitoylation of the human prostacyclin receptor. Functional implications of palmitoylation and isoprenylation. J Biol Chem. 2003 Feb 28;278(9):6947-58.
• [2] Molecular cloning of human prostacyclin receptor cDNA and its gene expression in the cardiovascular system. Circulation. 1994 Oct;90(4):1643-7.
• [3] Novel signaling pathways promote a paracrine wave of prostacyclin-induced vascular smooth muscle differentiation. J Mol Cell Cardiol. 2009 May;46(5):682-94.
• [4] 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.
• [5] 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.
• [6] The future potential of eicosanoids and their inhibitors in paediatric practice. Drugs. 1998 Aug;56(2):169-76.
• [7] Structural organization and chromosomal assignment of the human prostacyclin receptor gene. Genomics. 1995 May 1;27(1):142-8.
• [8] Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J. 2012 Oct;40(4):874-80.
• [9] 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.
• [10] Prostaglandin I2 IP Receptor Agonist, Beraprost, Prevents Transient Global Cerebral Ischemia Induced Hippocampal CA1 Injury in Aging Mice. J Neurol Disord. 2014;2:1000174.
• [11] 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.
• [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.
• [13] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [14] Protective effect of a prostaglandin I2 analog, TEI-7165, on ischemic neuronal damage in gerbils. Brain Res. 1997 Sep 26;769(2):321-8.
• [15] 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.
• [16] 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. (Target id: 345).
• [17] 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.
• [18] Molecular design of novel PGI2 agonists without PG skeleton, Bioorg. Med. Chem. Lett. 5(10):1071-1076 (1995).
• [19] Bioactivation of eptaloprost in animals and man. Prostaglandins. 1993 Aug;46(2):177-89.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [21] 7,7-Difluoroprostacyclin derivative, AFP-07, a highly selective and potent agonist for the prostacyclin receptor. Prostaglandins. 1997 Feb;53(2):83-90.
• [22] 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.
• [23] Relaxant actions of nonprostanoid prostacyclin mimetics on human pulmonary artery. J Cardiovasc Pharmacol. 1997 Apr;29(4):525-35.
• [24] 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.
• [25] 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.
• [26] Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics. Br J Pharmacol. 1986 Mar;87(3):543-51.
• [27] 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.
• [28] 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.
• [29] RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol. 2006 Feb;147(3):335-45.